Beta-amino acid nitrile derivatives as cathepsin K inhibitors

ABSTRACT

The present invention relates to beta-amino acid nitrile derivatives and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds are cysteine protease inhibitors useful for the treatment of diseases associated with cysteine proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease.

FIELD OF THE INVENTION

[0001] The present invention relates to novel beta-amino acid nitrilederivatives, their manufacture and use as medicaments. In particular,the invention relates to novel beta-amino acid nitrile derivatives offormula (I)

[0002] wherein

[0003] R¹ represents hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein

[0004] R^(a) represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy,

[0005] R^(b) represents aryl, aryl-lower-alkyl, or heteroaryl

[0006] R² represents hydrogen or lower-alkyl

[0007] R³ represents hydrogen or lower-alkyl

[0008] R⁴ represents hydrogen or lower-alkyl.

[0009] R⁵ represents hydrogen, lower-alkyl, cycloalkyl, or aryl,

[0010] n is 1 or 2,

[0011] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

BACKGROUND OF THE INVENTION

[0012] Cysteine proteases have been viewed as lysosomal mediators ofterminal protein degradation. Several newly discovered members of thisenzyme class, however, are regulated proteases with limited tissueexpression, which implies specific roles in cellular physiology and thuswould allow a specific targeting of these activities without interferingwith the general lysosomal protein degragation. Development ofinhibitors of specific cysteine proteases promises to provide new drugsfor modifying immunity, osteoporosis, neurodegeneration, chronicinflammation, cancer and malaria (Brömme, Drug News Perspect 1999,12(2), 73-82; Chapman et al., Annu. Rev. Phys. 1997, 59, 63-88).

[0013] Cysteine proteases can be grouped into two superfamilies: thefamily of enzymes related to interleukin 1_(β) converting enzyme (ICE),and the papain superfamily of cysteine proteases. Presently there are atleast 12 human proteases of the papain family from which sequences havebeen obtained (cathepsin B, L, H, S, O, K, C, W, F, V(L2), Z(X) andbleomycin hydrolase). Cathepsin K was first discovered as a cDNAprominent in rabbit osteoclasts and referred to as OC-2 (Tezuka et al.,J. Biol. Chem. 1994, 269, 1106-1109). Recent observations indicate thatcathepsin K is the most potent mammalian elastase yet described.Cathepsin K, as well as cathepsins S and L, are also potent collagenasesand gelatinases. Macrophages appear capable of mobilizing the activeproteases within endosomal and/or lysosomal compartments to the cellsurface under special circumstances. In this case, the cellsurface/substrate interface becomes a compartment from which endogenousinhibitors are excluded and can be viewed as a physiological extensionof the lysosome. This type of physiology is an innate trait ofosteoclasts, a bone macrophage, and may also be exploited by othermacrophages or cells in the context of inflammation. The abundance ofcathepsin K in osteoclasts leads to the suggestion that cathepsin Kplays an important role in bone resorption. Studies revealed thatcathepsin K is the predominant cysteine protease in osteoclasts and isspecifically expressed in human osteoclasts. A correlation betweeninhibition of cysteine protease activity and bone resorption has beenreported (Lerner et al., J. Bone Min. Res. 1992, 7, 433; Everts et al.,J. Cell. Physiol. 1992, 150, 221). Cathepsin K has been detected insynovial fibroblasts of RA patients, as well as in mouse hypertrophicchondrocytes (Hummel et al., J. Rheumatol. 1998, 25(10), 1887-1894.).Both results indicate a direct role of cathepsin K in cartilage erosion.P. Libby (Libby et al., J. Clin. Invest. 1998, 102 (3), 576-583)reported that normal arteries contain little or no cathepsin K or Swhereas macrophages in atheroma contained abundant immunoreactivecathepsins K and S. Most of the elastolytic activity of tissue extractsassociated with human atheroma compared to non-atherosclerotic arteriescould be inhibited with E64, a non-selective cysteine proteaseinhibitor.

[0014] Tumor progression and metastasis are characterized by theinvasion of tumors into adjacent tissues as well as by the dissociationof cancer cells from primary tumors and the infiltration of metastaticcells into organs. These processes are associated with the degragationof extracellular matrix proteins and thus require proteolytic activity.Cathepsin K has been identified in primary breast tumors, as well as inbreast tumor-derived bone metastasis (Littlewood-Evans et al., CancerRes. 1997, 57, 5386-5390).

[0015] Different classes of compounds, such as aldehydes, α-ketocarbonylcompounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methylketones, ketomethylsulfonium salts, epoxy succinyl compounds, vinylsulfones, aminoketones, and hydrazides have been identified as cysteineprotease inhibitors (Schirmeister et al., Chem. Rev. 1997, 97, 133-171;Veber et al., Proc. Natl. Acad. Sci. USA 1997, 94, 14249-14254). Theshortcomings these compounds suffer from include lack of selectivity,poor solubility, rapid plasma clearance and cytotoxicity. A needtherefore exists for novel inhibitors useful in treating diseases causedby pathological levels of proteases, especially cysteine proteases,including cathepsins, especially cathepsin K.

SUMMARY OF THE INVENTION

[0016] The beta-amino acid nitrile derivatives of formula (I) have aninhibitory activity on cysteine proteases, more paticulary on cysteineproteases of the papain superfamily, even more paticularly on cysteineproteases of the cathepsin family, most particularly on cathepsin K. Itwas surprisingly found, that this inhibiting effect on cathepsin K isselective with respect to other cathepsins. While compounds of formula(I) very efficiently inhibit cathepsin K, the inhibition of otherprotease inhibitors such as cathepsin S, cathepsin L and cathepsin B ismuch weaker. Therefore the new compounds of formula (I) are useful forspecifically inhibiting cathepsin K. They can accordingly be used forthe treatment of disorders which are associated with cysteine proteasessuch as osteoporosis, osteoarthritis, rheumatoid arthritis, tumormetastasis, glomerulonephritis, atherosclerosis, myocardial infarction,angina pectoris, instable angina pectoris, stroke, plaque rupture,transient ischemic attacks, amaurosis fugax, peripheral arterialocclusive disease, restenosis after angioplasty and stent placement,abdominal aortic aneurysm formation, inflammation, autoimmune disease,malaria, ocular fundus tissue cytopathy and respiratory disease.Accordingly, the present invention relates to a method for theprophylactic and/or therapeutic treatment of diseases which areassociated with cystein proteases such as osteoporosis, osteoarthritis,rheumatoid arthritis, tumor metastasis, glomerulonephritis,atherosclerosis, myocardial infarction, angina pectoris, instable anginapectoris, stroke, plaque rupture, transient ischemic attacks, amaurosisfugax, peripheral arterial occlusive disease, restenosis afterangioplasty and stent placement, abdominal aortic aneurysm formation,inflammation, autoimmune disease, malaria, ocular fundus tissuecytopathy and respiratory disease, which method comprises administeringa compound of formula (I) to a human being or an animal. The presentinvention also relates to pharmaceutical compositions comprising acompound of formula (I) and a pharmaceutically acceptable carrier and/oradjuvant. Furthermore, the present invention relates to the use of suchcompounds for the preparation of medicaments for the treatment ofdisorders which are associated with cystein proteases. The presentinvention also relates to processes for the preparation of the compoundsof formula (I).

DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise indicated the following definitions are setforth to illustrate and define the meaning and scope of the variousterms used to describe the invention herein.

[0018] In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

[0019] The term “alkyl” refers to a branched or straight chainmonovalent saturated aliphatic hydrocarbon radical of one to twentycarbon atoms, preferably one to sixteen carbon atoms. Alkyl groups canbe substituted e.g. with halogen atoms.

[0020] The term “lower-alkyl” refers to a branched or straight chainmonovalent alkyl radical of one to seven carbon atoms, preferably one tofour carbon atoms. This term is further exemplified by such radicals asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and thelike.

[0021] The term “cycloalkyl” refers to a monovalent carbocyclic radicalof 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.

[0022] The term “halogen” refers to fluorine, chlorine, bromine andiodine, with fluorine, chlorine and bromine being preferred and chlorineand bromine being more preferred.

[0023] The term “alkoxy” refers to the group R′—O—, wherein R′ is analkyl. The term “lower-alkoxy” refers to the group R′—O—, wherein R′ isa lower-alkyl.

[0024] The term “alkenyl” stands for alone or in combination with othergroups, a straight-chain or branched hydrocarbon residue containing anolefinic bond and up to 20, preferably up to 16 C-atoms. The term“lower-alkenyl” refers to a straight-chain or branched hydrocarbonresidue containing an olefinic bond and up to 7, preferably up to 4C-atoms.

[0025] The term “aryl” relates to the phenyl or naphthyl group which canoptionally be mono- or multiply-substituted by alkyl, halogen, hydroxy,nitro, cyano, —CF₃, acetyl, acetyl-amino, —SCH₃, alkoxy,alkylcarbonyloxy, aryl, aryloxy, or aryl-alkoxy. Preferred substituentsare lower-alkyl, fluorine, chlorine, bromine, hydroxy, lower-alkoxy,lower-alkylcarbonyloxy, phenyl, phenoxy, aryl-lower-alkyl, andaryl-lower-alkoxy. More preferred substituents are hydroxy, methyl,chlorine, bromine, and methoxy. The term aryl further relates to asubstituted phenyl group which is the benzo[1,3]dioxol-5-yl group.

[0026] The term “heteroaryl” refers to an aromatic 5- or 6-membered ringwhich can contain 1, 2 or 3 atoms selected from nitrogen, oxygen orsulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, with furyl and thienyl beingpreferred. The term “heteroaryl” further refers to bicyclic aromaticgroups comprising 2 5- or 6-membered rings, in which one or both ringscan contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphursuch as e,g, benzo[1,2,5]oxadiazole or benzofuranyl. A heteroaryl groupmay have a substitution pattern as described earlier in connection withthe term “aryl”.

[0027] The term “pharmaceutically acceptable salts” embraces salts ofthe compounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonicacid and the like, which are non toxic to living organisms.

[0028] The term “pharmaceutically acceptable esters” embraces esters ofthe compounds of formula (1), in which hydroxy groups have beenconverted to the corresponding esters with inorganic or organic acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulphuricacid, phosphoric acid, citric acid, formic acid, maleic acid, aceticacid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

[0029] The term “isolated sterioisomer” refers to a compoundsubstantially free of isomers having different conformations at anychiral centers having a specified conformation in the compound's formulaor name.

[0030] The term “therapeutically effective amount” refers to that amountof a compound which, when administered to a patient having a cysteineprotease associated condition, ameliorates or relieves one or moresymptoms of that condition.

[0031] In detail, the present invention refers to compounds of formula(I)

[0032] wherein

[0033] R¹ represents hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein

[0034] R^(a) represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy,

[0035] R^(b) represents aryl, aryl-lower-alkyl, or heteroaryl

[0036] R² represents hydrogen or lower-alkyl

[0037] R³ represents hydrogen or lower-alkyl

[0038] R⁴ represents hydrogen or lower-alkyl.

[0039] R⁵ represents hydrogen, lower-alkyl, cycloalkyl, or aryl,

[0040] n is 1 or 2,

[0041] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

[0042] The compounds of formula (I) have at least 2 asymmetric carbonatoms and can exist in the form of optically pure enantiomers or asracemates. The invention embraces all of these forms. Preferredcompounds of formula (I) are compounds of formula (Ia)

[0043] wherein R¹, R², R³, R⁴, R⁵ and n have the significances givenabove and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof. The compounds of formula (Ia) encompass cis-as well as trans-compounds. Other preferred compounds of formula (I) arecis-compounds of formula (Ib)

[0044] wherein R¹, R², R³, R⁴, R⁵ and n have the significances givenabove and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof. Further preferred compounds of formula (I)are compounds of formula (Ic)

[0045] wherein R¹, R², R³, R⁴, R⁵ and n have the significances givenabove and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof. The compounds of formula (Ic) encompassescis- as well as trans-compounds.

[0046] Compounds of formula (I) in which n is 2 are preferred. Compoundsof formula (I) in which R², R³, and/or R⁴ represent hydrogen are alsopreferred. Another preferred embodiement refers to compounds of formula(I) in which R⁵ is aryl, particularly those compounds in which R⁵ isphenyl or naphthyl, optionally substituted with lower-alkyl, halogen,hydroxy, lower-alkoxy, or lower-alkyl-carbonyloxy, or in which R⁵ isbenzo[1,3]dioxyl. Further, compounds of formula (I) in which R⁵represents phenyl or naphthyl, optionally substituted with hydroxy,methoxy, methyl, acetoxy, chlorine or bromine, or wherein R⁵ isbenzo[1,3]dioxyl are also preferred with phenyl, 3-hydroxy-phenyl,3-methoxy-phenyl, 4-methoxy-phenyl, 3-methyl-phenyl,2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3-chloro-phenyl,3-bromo-phenyl, 4-bromo-phenyl, or benzo [1,3] dioxol-5-yl beingespecially preferred. Other preferred compounds of formula (I) are thosewherein R⁵ is hydrogen. Further preferred compounds of formula (I) arethose wherein R⁵ is cycloalkyl, more preferably cyclopropyl.

[0047] Compounds of formula (I) in which R¹ represents —CO—R^(a) andR^(a) is as defined above are preferred. Compounds of formula (I) inwhich R¹ represents —CO—R^(a) and R^(a) is cycloalkyl,cycloalkly-lower-alkyl, cycloalkyloxy, aryl, aryloxy, aryl-lower-alkyl,aryl-lower-alkoxy, aryloxy-lower-alkyl, aryl-S-lower-alkyl,aryl-lower-alkenyl, or heteroaryl-lower-alkoxy are especially preferred.A further preferred embodiement are compounds of formula (I) in which R¹represents —CO—R^(a) and R^(a) is phenyl, optionally substituted withphenyl, cyano, and/or fluoro, or R^(a) is benzyloxy optionallysubstituted with methyl, chloro, fluoro, methoxy, nitro, and/or CF₃, orR^(a) is phenylvinylene, thiophenyl-methylene-oxy, cyclopentyloxy,thiophenyl-ethylene-oxy, naphthyloxy, thiophenyl-trimethylene-oxy, orphenoxy. Particularly preferred are compounds of formula (I) wherein R¹represents —CO—R^(a) and R^(a) is benzyloxy, phenylvinylene,thiophen-2-yl-methylene-oxy, or thiophen-3-yl-methylene-oxy. Anotherpreferred embodiment relates to compounds of formula (I) wherein R¹represents —SO₂—R^(b) and R^(b) is as defined above. Preferrably R^(b)represents phenyl optionally substituted with chlorine, cyano and/ormethylcarbonyl-amino, or R^(b) is benzyl or benzo[1,2,5]oxadiazole. Mostpreferrably, R^(b) represents 4-chloro-phenyl. A further preferredembodiment relates to compounds of formula (I) wherein R¹ representsphenyl optionally substituted with ethoxy. Other preferred compounds offormula (I) are those wherein R¹ represents —CO—R^(a) and R^(a) isbenzyl optionally substituted with chloro, or phenyl optionallysubstituted with lower-alkyl, lower-alkoxy, or cyano, preferably thosewherein R^(a) is 4-ethyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl,4-cyano-phenyl, 4-tert.-butyl-phenyl, or 4-chloro-benzyl. Furtherpreferred compounds of the present invention are those wherein R¹represents —CO—R^(a) and R^(a) is heteroaryl, preferably those in whichR^(a) is 5-methoxy-benzofuran-2-yl.

[0048] Preferred compounds of formula (I) are those selected from thegroup consisting of(1R,2R)-(2-{(S)-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0049] cis-2-(3-Phenyl-acryloylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0050](R)-{2-[(S)-(Cyano-phenyl-methyl)-(R)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0051] syn-{2-[(S)-(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester,

[0052] cis-(2-{(R)- and(S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0053] trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0054] trans-{2-[(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester,

[0055]cis-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0056]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0057] cis-2-(3-Phenyl-acryloylamino-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide,

[0058](2-{[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester (1 cis-racemate),

[0059] cis-{2-[(R)- and(S)-(Cyano-m-tolyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester,

[0060](2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-3-ylmethyl ester,

[0061] cis-(2-{(R)- and(S)-[Cyano-(4-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0062] cis-(2-{(R)- and(S)-[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0063]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-2-ylmethyl ester,

[0064] cis-(2-{(R)- and(S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0065] cis-{2-[(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0066]trans-(2-{[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0067] cis-(2-{(R)- and(S)-[(4-Bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamic acidbenzyl ester,

[0068] cis-(2-{[(R)- and(S)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid cyclopentyl ester,

[0069]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamic acid 2-thiophen-2-yl-ethyl ester,

[0070]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-methyl-benzyl ester,

[0071] trans-2-Phenylmethanesulfonylamino-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0072] trans-(2-{[Cyano-(3 -hydroxy-phenyl)- methyl]- carbamoyl}-cyclohexyl)-carbamic acid 2-chloro-benzyl ester,

[0073] cis-(2-{(R)- and(S)-[(4-Chloro-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0074](2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-fluoro-benzyl ester,

[0075] cis-{2-[(R)- and(S)-(Cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acidnaphthalen-2-yl ester,

[0076] cis-{2-[(R)- and(S)-(Cyano-naphthalen-2-yl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester,

[0077]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-thiophen-2-yl-propyl ester,

[0078] trans-2-(4-Cyano-benzenesulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0079]trans-(2-{[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0080] cis-Acetic acid 4-(R)- and(S)-[(2-benzyloxycarbonylamino-cyclohexanecarbonyl)-amino]-cyano-methyl}-phenylester,

[0081] trans-{2-[(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0082] cis-N-(2-{[(R)- and(S)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-benzamide,

[0083]trans-(2-{[(3-Bromo-4-methoxy-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0084] cis-{2-[(R)- and(S)-(Cyano-naphthalen-1-yl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester,

[0085]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-methoxy-benzyl ester,

[0086] (1R,2R)-(2-{(R)-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0087]trans-(2-{[(3-Bromo-4-methoxy-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0088] trans-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid benzylester,

[0089]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-chloro-benzyl ester,

[0090]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-methyl-benzyl ester,

[0091] cis-Biphenyl-4-carboxylic acid (2-{[(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide,

[0092] cis-{2-[(R)- and(S)-(Cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acid phenylester,

[0093]trans-2-(4-Acetylamino-benzenesulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0094] cis-N-{2-[(R)- and(S)-(Cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-benzamide,

[0095]trans-2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-methoxy-benzyl ester,

[0096]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-methyl-benzyl ester,

[0097] cis-{2-[(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester,

[0098]trans-4-Cyano-N-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-benzamide,potrans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-methoxy-benzyl ester,

[0099] cis-2-(3-Cyclopentyl-propionylamino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0100](2-{[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester (1 cis-racemate),

[0101] cis-{2-[(R)- and(S)-(Cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acid4-nitro-benzyl ester,

[0102] cis-(2-{[(R)- and(S)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-nitro-benzyl ester,

[0103] cis-2-(3-Phenyl-propionylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0104] cis-2-(Cyclopropanecarbonyl-amino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0105] cis-{2-[(R)- and(S)-(Cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acidcyclopentyl ester,

[0106]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-p-tolyl-propyl ester,

[0107] cis-[2-((R)- and(S)-1-Cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-carbamic acid benzylester,

[0108] cis-2-(2-Phenoxy-acetylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0109] trans-2-(2-Phenoxy-acetylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0110] cis-(2-{(R)- and(S)-[Cyano-(2,4-dimethyl-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0111] cis-2-[2-(4-Chloro-phenoxy)-acetylamino]-cyclohexanecarboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0112] cis-2-(2-Phenylsulfanyl-acetylamino-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide,

[0113]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-(4-chloro-phenyl)-propyl ester,

[0114] cis-2-(2-Phenylsulfanyl-acetylamino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0115] trans-2-(Benzo [1,2,5]oxadiazole-4-sulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0116]trans-N-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-4-fluoro-benzamide,

[0117] cis-2-[2-(4-Chloro-phenoxy-acetylamino]-cyclohexanecarboxylicacid ((R)- and (S)-cyano-phenyl-methyl-amide,

[0118] cis-2-(3-Phenyl-propionylamino)-cyclohexanecarboxylic acid(cyano-phenyl-methyl)-amide,

[0119] cis-2-Phenylacetylamino-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0120] cis-2-Phenylmethanesulfonylamino-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0121] trans-2-(2-Phenylsulfanyl-acetylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0122] cis-[2-((R)- and (S)-1-Cyano-hexylcarbamoyl)-cyclohexyl]-carbamicacid benzyl ester

[0123] cis-2-(2-Phenoxy-acetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide,

[0124] trans-Isoxazole-5-carboxylic acid(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide,

[0125] cis-2-(3-Cyclohexylcarbonylamino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0126](2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-trifluoromethyl-benzyl ester,

[0127] cis-2-(Cyclobutanecarbonyl-amino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0128] cis-2-[2-(4-Chloro-phenyl-acetylamino]-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide,

[0129] cis-2-(Cyclopentanecarbonyl-amino-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide,

[0130] cis-2-[2-(4-Chloro-phenyl)-acetylamino]-cyclohexanecarboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0131] (1S,2R)-{2-(R)- and(S)-[(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester,

[0132] (1S,2R)-(2-(R)- and(S)-{[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0133]trans-N-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-4-fluoro-benzamide,

[0134] cis-2-(2-Benzyloxy-acetylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0135] trans-2-(2-Thiophen-2-yl-acetylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0136] cis-[2-((R)- and(S)-1-Cyano-propylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester,

[0137] cis-2-Phenylacetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide,

[0138] cis-2-(2-Benzyloxy-acetylamino-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide,

[0139] cis-2-(Cyclopropanecarbonyl-amino-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide,

[0140] cis-2-(3-Cyclopentyl-propionylamino-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide,

[0141] cis-2-(Cyclopentanecarbonyl-amino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0142] trans-Thiophene-2-carboxylic acid(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide,

[0143] cis-2-(3-Phenyl-propionylamino-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide,

[0144] cis-2-Phenylmethanesulfonylamino-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide,

[0145]trans-(2-{[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0146] cis-2-(4-Ethoxy-phenylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0147] 2-(4-Ethoxy-phenylamino)-cyclohexanecarboxylic acid(cyano-phenyl-methyl)-amide,

[0148] cis-2-(4-Ethoxy-phenylamino)-cyclohexanecarboxylic acid[(3-bromo-phenyl)-cyano-methyl]-amide,

[0149] cis-2-(4-Ethoxy-phenylamino)-cyclohexanecarboxylic acid(benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,

[0150] cis-2-(4-Ethoxy-phenylamino)-cyclohexanecarboxylic acid[cyano-(4-methoxy-phenyl)-methyl]-amide,

[0151] cis-2-Phenylamino-cyclohexanecarboxylic acid(benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,

[0152] 2-Phenylamino-cyclohexanecarboxylic acid(cyano-phenyl-methyl)-amide,

[0153] cis-(2-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclopentyl)-carbamicacid benzyl ester,

[0154]trans-(2-{[(3-Chloro-phenyl-cyano-methyl]-carbamoyl}-cyclopentyl-carbamicacid benzyl ester,

[0155]trans-(2-{[Cyano-(3-methoxy-phenyl-methyl]-carbamoyl}-cyclopentyl-carbamicacid benzyl ester,

[0156] trans-{2-[(Cyano-phenyl-methyl-carbamoyl]-cyclopentyl}-carbamicacid benzyl ester, and

[0157] trans-{2-[(Cyano-m-tolyl-methyl-carbamoyl]-cyclopentyl}-carbamicacid benzyl ester,

[0158] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

[0159] Especially preferred compounds of formula (I) are

[0160](1R,2R)-(2-{(S)-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0161] cis-2-(3-Phenyl-acryloylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0162](R)-{2-[(S)-(Cyano-phenyl-methyl)-(R)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0163] syn-{2-[(S)-(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0164] cis-(2-{(R)- and(S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0165] trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide,

[0166] trans-{2-[(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester,

[0167]cis-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0168]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0169] cis-2-(3-Phenyl-acryloylamino-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide,

[0170](2-{[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester (1 cis-racemate),

[0171] cis-{2-[(R)- and(S)-(Cyano-m-tolyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester,

[0172](2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-3-ylmethyl ester,

[0173] cis-(2-{(R)- and(S)-[Cyano-(4-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0174] cis-(2-{(R)- and(S)-[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0175]trans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-2-ylmethyl ester,

[0176] cis-(2-{(R)- and(S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0177] cis-{2-[(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester,

[0178]trans-(2-{[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester,

[0179] cis-(2-{(R)- and(S)-[(4-Bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamic acidbenzyl ester, and

[0180] cis-(2-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclopentyl)-carbamicacid benzyl ester,

[0181] and pharmaceutically acceptable esters thereof.

[0182] Other preferred compounds of formula (I) are those selected fromthe group consisting of

[0183] Cis{2-[(Cyano- cyclopropyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzyl ester,

[0184] Cis-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-chloro-benzyl ester,

[0185] Cis-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-bromo-benzyl ester,

[0186] Cis-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3-nitro-benzyl ester,

[0187] Cis-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid4-chloro-benzyl ester,

[0188] Cis-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3,4-dichloro-benzyl ester,

[0189] Cis-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3-choro-benzyl ester,

[0190] Trans-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]- carbamic acid2-chloro-benzyl ester,

[0191] Trans-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-bromo-benzyl ester,

[0192] Trans-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3-nitro-benzyl ester,

[0193] Trans-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid phenylester,

[0194] Trans-[4-(Cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3,4-dichloro-benzyl ester,

[0195] Cis-5-Methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide,

[0196] Trans-5-Methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide,

[0197]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2-chloro-4-fluoro-benzamide,

[0198] Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2-methoxy-3-methyl-benzamide,

[0199]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,6-dichloro-4-methoxy-benzamide,

[0200] Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-fluoro-4-methyl-benzamide,

[0201]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-4-methyl-benzamide,

[0202]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-bromo-4-methyl-benzamide,

[0203]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-cyanomethyl-benzamide,

[0204]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3,5-di-trifluoromethyl-benzamide,

[0205]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-tert-butyl-benzamide,

[0206]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-6-methoxy-benzamide,

[0207]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-6-methoxy-benzamide,

[0208] Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-benzamide,

[0209]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-acetylamino-benzamide,

[0210]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3-acetylamino-benzamide,

[0211]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-acetylamino-benzamide,

[0212]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-acetylamino-benzamide,

[0213] Cis-N-[2-(Cyanomethyl-carbamoyl)-cylohexyl]-4-acetyl-benzamide,

[0214]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-acetyl-benzamide,

[0215]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2-chloro-5-(methylthio)-benzamide,

[0216] Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,3-dichloro-benzamide,

[0217]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,3-dichloro-benzamide,

[0218] Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,4-dichloro-benzamide,

[0219] Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,5-dichloro-benzamide,

[0220]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-2,6-dichloro-benzamide,

[0221]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3,4-dichloro-benzamide,

[0222]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3,4-dichloro-benzamide,

[0223]Cis-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3,4-dichloro-benzamide,

[0224]Trans-N-[2-(Cyanomethyl-carbamoyl)-cyclohexyl]-3,5-dichloro-benzamide,

[0225]Cis-2-{[2(4-chlorophenyl)acetyl]amino}-N-[cyano(cyclopropyl)methyl]cyclohexanecarboxamide,

[0226] Cis-N-[cyano(cyclopropyl)methyl]-2-{[3-(3-methoxyphenyl)propanoyl]amino}cyclohexanecarboxamide,

[0227]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

[0228]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzamide,

[0229]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

[0230]Trans-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

[0231]Trans-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

[0232]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-3,4-difluorobenzamide,

[0233]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzamide,

[0234]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert-butylbenzamide,and

[0235]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-3,4,5-trimethoxybenzamide,

[0236] and pharmaceutically acceptable esters thereof.

[0237] Other especially preferred compounds of formula (I) are

[0238] Cis-5-Methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide,

[0239] Trans-5-Methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide,

[0240]Cis-2-{[(4-chlorophenyl)acetyl]amino}-N-[cyano(cyclopropyl)methyl]cyclo-hexanecarboxamide,

[0241]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

[0242]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzamide,

[0243]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

[0244]Trans-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

[0245]Trans-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

[0246]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzamide,and

[0247]Cis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert-butylbenzamide,

[0248] and pharmaceutically acceptable esters thereof.

[0249] The invention also relates to the use of compounds of formula (I)as defined above for the treatment or prophylaxis of diseases which areassociated with cysteine proteases such as osteoporosis, osteoarthritis,rheumatoid arthritis, tumor metastasis, glomerulonephritis,atherosclerosis, myocardial infarction, angina pectoris, instable anginapectoris, stroke, plaque rupture, transient ischemic attacks, amaurosisfugax, peripheral arterial occlusive disease, restenosis afterangioplasty and stent placement, abdominal aortic aneurysm formation,inflammation, autoimmune disease, malaria, ocular fundus tissuecytopathy and respiratory disease. In a preferred embodiement, theinvention relates to the use of compounds as defined above for thetreatment or prophylaxis of osteoporosis, instable angina pectoris orplaque rupture.

[0250] Further, the invention relates to compounds as defined above foruse as therapeutic active substances, in particular in context withdiseases which are associated with cysteine proteases such asosteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease. In a preferredembodiement, the invention relates to compounds as defined above for useas therapeutic active substances, in particular in context withosteoporosis, instable angina pectoris or plaque rupture.

[0251] The invention also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant, in particular for use in context with diseaseswhich are associated with cysteine proteases such as osteoporosis,osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease. In a preferredembodiement, the invention relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant for use in context with osteoporosis, instableangina pectoris or plaque rupture.

[0252] A further embodiment of the present invention refers to the useof compounds as defined above for the preparation of medicaments for thetreatment or prophylaxis of diseases which are associated with cysteinproteases such as osteoporosis, osteoarthritis, rheumatoid arthritis,tumor metastasis, glomerulonephritis, atherosclerosis, myocardialinfarction, angina pectoris, instable angina pectoris, stroke, plaquerupture, transient ischemic attacks, amaurosis fugax, peripheralarterial occlusive disease, restenosis after angioplasty and stentplacement, abdominal aortic aneurysm formation, inflammation, autoimmunedisease, malaria, ocular fundus tissue cytopathy and respiratorydisease. In a preferred embodiement, the invention relates to the use ofcompounds as defined above for the preparation of medicaments for thetreatment or prophylaxis of osteoporosis, instable angina pectoris orplaque rupture. Such medicaments comprise a compound as defined above.

[0253] An additional embodiment of the invention relates to a method forthe prophylactic and/or therapeutic treatment of disorders in whichcathepsin K plays a significant pathological role, such as osteoporosis,osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease, which methodcomprises administering a compound as defined above to a human being oran animal. A preferred embodiement of the invention relates to a methodfor the prophylactic and/or therapeutic treatment of osteoporosis,instable angina pectoris or plaque rupture, which method comprisesadministering a compound as defined above to a human being or an animal.

[0254] The invention further relates to a process for the manufacture ofcompounds of formula (I) which process comprises

[0255] reacting a compound of formula (II)

[0256] wherein R¹, R², R³, R⁴, R⁵, and n have the significances givenabove, or

[0257] wherein R², R³, R⁴, R⁵, R^(a), R^(b) and n have the significancesgiven above.

[0258] The invention also relates to a process as described above, whichprocess comprises the preparation of pharmaceutically acceptable saltsand/or pharmaceutically acceptable esters. The formation of the estersand/or salts can be carried out at different stages of the process, e.g.with the compound of formula (I) or with the corresponding startingmaterials.

[0259] The reaction of a compound of formula (II) with a compound offormula (III) can be carried out by methods known to the person skilledin the art. The reaction can conveniently be carried out by dissolvingcompound (II), compound (III), TPTU(O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate) and Hünigsbase (N-Ethyldiisopropylamine) in MeCN andstirring the mixture at room temperature for 6 to 16 hours. The reactionmixture can be concentrated and the product can be obtained by methodsknown to the person skilled in the art, e.g. by extraction and columnchromatography. Alternatively, a compound of formula (II) can bedissolved in CH₂Cl₂ and reacted for 6 to 16 hours at room temperaturewith a compound of formula (III) in the presence of N-methylmorpholin,HOBT and EDCI. The product can be isolated by methods known per se, e.g.by extraction and HPLC.

[0260] The reaction of a compound of formula (IV) with a compound offormula (V) or (VI) is conveniently carried out by preparing a solutionof compound (IV) in CH₂Cl₂ and adding a solution of compound (V) or (VI)in CH₂Cl₂. To this mixture, Triethylamin is added and after shaking 6 to16 hours at room temperature formic acid is added. The product can beisolated and purified by methods known per se, e.g. by evaporation ofthe solvent and HPLC.

[0261] In order to prepare pharmaceutically acceptable salts and/orpharmaceutically acceptable esters of compounds of formula (I), it ispossible to prepare the corresponding esters and/or salts starting fromthe compounds of formula (I). It is also possible, to form the estersand/or salts at an earlier stage, e.g. to form the corresponding saltsan/or esters of the corresponding starting materials. The methods toprepare pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters as defined before are known in the art.

[0262] Compounds of formula (II) are prepared by methods known to theperson skilled in the art. See, for example, the procedures cited in thenovabiochem 2000 catalog, pp. 1-34. Conveniently, the correspondingamino acid is linked to the desired substituent R¹ analogously to themethods described in the examples. The resulting compound (II) isisolated by methods known per se, e.g. by extraction and evaporation ofthe solvent.

[0263] Compounds of formula (III) can conveniently be obtained by addinga solution of the corresponding aldehyde in CH₂Cl₂ to a solution ofNH₄Cl and NaCN in H₂O and MeOH at 0° C. The corresponding aldehydes areavailable from Aldrich or can be prepared by methods known in the artfrom aldehydes available from Aldrich. The mixture is stirred andallowed to warm to room temperature. After addition of NH₃ solution andcompletion of the reaction the resulting compound of formula (III) isisolated and purified by methods known to the person skilled in the art,e.g. by extraction. The corresponding hydrochlorid can be prepared bymethods known per se.

[0264] Chiral compounds of formula (III) can conveniently be obtained byadding ammonium bicarbonate to a mixed anhydride (prepared from asuitable t-BOC protected amino acid and di-tert-butyl dicarbonate) at15° C. The reaction mixture is stirred at room temperature for 1-5 h.After completion of the reaction the resulting t-BOC protected aminoacid amide is isolated and purified by methods known to the personskilled in the art, e.g. by extraction. The Boc protected amino acidamide and triethylamine are dissolved in THF and trifluoroacetic acidanhydride at 0° C. The mixture is stirred for 2 h at −10° C. Afterisolation and purification of the resulting intermediate product, e.g.by evaporation of the solvent and flash chromatography, the t-BOCprotective group can be cleaved off with HCl in acetic acid to yield thedesired compound of formula (III).

[0265] Compounds of formula (IV) can conveniently be obtained byreacting the corresponding t-BOC protected amino acid with a compound offormula (III) analogous to the method described above. The correspondingt-BOC protected amino acids can be prepared by methods known to theperson skill in synthetic organic chemistry. See, for example,procedures cited in novabiochem 2000 calatog above. After isolation andpurification of the resulting intermediate product, e.g. by evaporationof the solvent and flash chromatography, the t-BOC protective group canbe cleaved off with trifluoro-acetic acid to yield the desired compoundof formula (IV) with trifluoro-acetic acid.

[0266] Compounds of formula (V) and (VI) are either commerciallyavailable or can be obtained by methods known in the art.

[0267] The following scheme (corresponds to method G in the experimentalsection) shows another possibility to prepare compounds of the presentinvention by solid phase synthesis.

[0268] To 1 eq of Rink resin bound glycine (see Rink, Tetrahedron Lett.1987, 28, 3787) in DMF is added 1 eq of educt 1 (a cyclohexanecarboxylicacid derivative available from Aldrich or Acros), EDCI, HOBT, and NMM(N-methylmorpholine). The reaction is shaken overnight at RT. Thesolvent is removed and the resin washed with dichloromethane, methanol,and again with dichloromethane. The resin is then suspended in DMF and20% piperidine is added. After 30 minutes reaction time at RT, thesolvent is removed by filtration. The resin is washed withdichloromethane, methanol, and again with dichloromethane. The resin isagain suspended in DMF and 3 eq. of the corresponding succinimidylcarbonate (educt 2, available from Aldrich or Acros) is added. Thereaction is shaken overnight at RT. The resin is then filtered andwashed with dichloromethane, methanol, and again with dichloromethane.The resin is then suspended in a 10% solution of trifluoroacetic acid indichloromethane. After 30 minutes reaction time at room temperature, theresin is filtered and washed with dichloromethane. The filtrate isconcentrated to dryness to yield the amide. The amide is subjected todehydration using Burgess reagent(Methoxycarbonylsulfamoyl-triethylammonium hydroxide, see Burgess, E. M.Atkins, G. M. J. Am. Chem. Soc. 1968, 90, 4744). The amide is diluted indichloromethane or in the trans case 1,4-dioxane. One eq. of Burgessreagent is added and the reaction is stirred for 2 h at RT, afterwhich asecond eq. of Burgess is added and the reaction is stirred for anadditional 2 h. The crude reaction mixture is evaporated to dryness andthen diluted in ethyl acetate. The desired compound is isolated andpurified by methods known to the person skilled in the art, e.g byextraction and by preparative HPLC.

[0269] The following scheme (corresponds to method H in the experimentalsection) shows another possibility to prepare compounds of the presentinvention by solid phase synthesis.

[0270] To 1 eq of Rink resin bound glycine (see Rink, Tetrahedron Lett.1987, 28, 3787) in DMF is added 1 eq. of educt 1 (acyclohexanecarboxylic acid derivative), EDCI, HOBT, and NMM. Thereaction is shaken overnight at RT. The solvent is removed and the resinwashed with dichloromethane, methanol, and again with dichloromethane.The resin is then suspended in DMF and 20% piperidine is added. After 30minutes reaction time at RT, the solvent is removed by filtration. Theresin is washed with dichloromethane, with methanol, and again withdichloromethane. The resin is again suspended in DMF and 3 eq. thecorresponding carboxylic acid (educt 2) is added, along with EDCI, HOBT,and NMM. The reaction is shaken overnight at RT. The resin is thenfiltered and washed with dichloromethane, methanol, and again withdichloromethane. The resin is then suspended in a 10% solution oftrifluoroacetic acid in dichloromethane. After 30 minutes reaction timeat RT, the resin is filtered and washed with dichloromethane. Thefiltrate is concentrated to dryness to yield the amide. The amide issubjected to dehydration using Burgess reagent(Methoxycarbonylsulfamoyl-triethylammonium hydroxide, see Burgess, E. M.Atkins, G. M. J. Am. Chem. Soc. 1968, 90, 4744). The amide is diluted indichloromethane or in the trans case 1,4-dioxane. One eq. of Burgess isadded and the reaction stirred for 2 h at RT, afterwhich a second eq. ofBurgess is added and the reaction stirred for an additional 2 h. Thecrude reaction mixture is evaporated to dryness and then diluted inethyl acetate. The desired compound is isolated and purified by methodsknown to the person skilled in the art, e.g by extraction and bypreparative HPLC.

[0271] All educts used to prepare compounds by solid phase synthesis areeither commercially available or can be obtained by methods known in theart or by methodes described herein.

[0272] The following scheme (corresponds to methods I and F in theexperimental section) shows another possibility to prepare compounds ofthe present invention.

[0273] I) HOBT is added to a solution of the acid in DMF. The mixture isstirred at room temperature for 1 hour and 2-Amino-cyclohexanecarboxylicacid(l-cyano-1-cyclopropyl-methyl)-amide acetic acid salt, EDCI and NMM(N-methylmorpholine) are added. The mixture is stirred at roomtemperature overnight and concentrated. The desired compound is isolatedand purified by methods known to the person skilled in the art, e.g byextraction and by preparative TLC. Starting materials for this methodcan be purchased from Aldrich or Acros or can be prepared from reagentspurchased from Aldrich or Acros by methods known in the art.

[0274] F) DIPEA (diisopropylethylamine) is added to a solution of2-Amino-cyclohexanecarboxylic acid(1-cyano-1-cyclopropyl-methyl)-amideacetic acid salt in CH₂Cl₂. The mixture is stirred at room temperaturefor 45 minutes. The acid chloride is added and the reaction mixture isstirred at room temperature under N₂ overnight. The desired compound isisolated and purified by methods known to the person skilled in the art,e.g by extraction and by preparative TLC (PathF). Starting materials forthis method can be purchased from Aldrich or Acros or can be preparedfrom reagents purchased from Aldrich or Acros by methods known in theart.

[0275] The isolated cis- and trans-forms of the product are obtained bystarting from the corresponding cis- or trans-form of the cyclohexanederivative.

[0276] The present invention relates to all compounds of formula (I), asprepared by one of the processes described above.

[0277] The invention also relates to compounds of formula (IV)

[0278] wherein R², R³, R⁴, R⁵ and n are as defined above.

[0279] The inhibitory activity of the compounds against cathepsin K, S,L and B was tested at room temperature in 96-wells opaque whitepolystyrene plates (Costar). The cathepsin K inhibitory activity wastested as follows:

[0280] 5 μl of an inhibitor diluted in 5 mM sodium phosphate, NaCl 15 mMpH 7.4 containing 1% DMSO (final concentrations: 10-0.0001 μM) werepreincubated for 10 min with 35 μl of human recombinant cathepsin K(final concentration: 1 nM) diluted in assay buffer (100 mM sodiumacetate pH 5.5 containing 5 mM EDTA and 20 mM cysteine). After additionof 10 μl of the fluorogenic substrate Z—Leu—Arg—MCA diluted in assaybuffer (final concentration: 5 pM), increase of fluorescence (excitationat 390 nm and emission at 460 nm) was measured for 7.5 min every 45 sec.The initial velocity (RFU/min) was derived from the linear fit of the 11reading points.

[0281] The cathepsin B inhibitory activity was assayed under the sameconditions as the cathepsin K inhibitory activity using human livercathepsin B (Calbiochem) at a final concentration of 1 nM.

[0282] The cathepsin L inhibitory activity was assayed under the sameconditions as the cathepsin K inhibitory activity using human livercathepsin L (Calbiochem) at a final concentration of 3 nM.

[0283] Cathepsin S inhibitory activity was assayed analogeously to thecathepsin K inhibitory activity, except that the buffer was 100 mMpotassium phosphate, 5mM EDTA, 5mM DTT (freshly added), 0.01% TritonX-100, pH 6.5 and the fluorogenic substrate was Z—Val—Val—Arg—MCA(Bachem) (final concentration: 20 μM). Human recombinant cathepsin S(Wiederanders et al., Eur. J. Biochem. 1997, 250, 745-750) was used at afinal concentration of 0.5 nM.

[0284] The results are given as IC₅₀ values which denote theconcentration of the inhibitor at which the enzymatic activity isinhibited by 50%. The IC₅₀ values are determined from a linearregression curve from a logit-log plot. Cathepsin K Cathepsin SCathepsin L Cathepsin B Example IC₅₀ (μMol/l) IC₅₀ (μMol/l) IC₅₀(μMol/l) IC₅₀ (μMol/l) 8.1 0.005 >10 4.7 4.6 8.2 0.016 0.64 1.2 0.0958.15 0.016 1.26 0.58 0.44 8.12 0.029 2.61 1.38 0.64 8.7 0.027 >10 4.691.38

[0285] It will be appreciated that the compounds of formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compounds in vivo.

[0286] As mentioned earlier, medicaments containing a compound offormula (I) are also an object of the present invention, as is a processfor the manufacture of such medicaments, which process comprisesbringing one or more compounds of formula (I) and, if desired, one ormore other therapeutically valuable substances into a galenicaladministration form.

[0287] The pharmaceutical compositions may be administered orally, forexample in the form of tablets, coated tablets, dragees, hard or softgelatine capsules, solutions, emulsions or suspensions. Administrationcan also be carried out rectally, for example using suppositories;locally or percutaneously, for example using ointments, creams, gels orsolutions; or parenterally, e.g. intravenously, intramuscularly,subcutaneously, intrathecally or transdermally, using for exampleinjectable solutions. Furthermore, administration can be carried outsublingually or as opthalmological preparations or as an aerosol, forexample in the form of a spray.

[0288] For the preparation of tablets, coated tablets, dragees or hardgelatine capsules the compounds of the present invention may be admixedwith pharmaceutically inert, inorganic or organic excipients. Examplesof suitable excipients for tablets, dragees or hard gelatine capsulesinclude lactose, maize starch or derivatives thereof, talc or stearicacid or salts thereof.

[0289] Suitable excipients for use with soft gelatine capsules includefor example vegetable oils, waxes, fats, semi-solid or liquid polyolsetc.; according to the nature of the active ingredients it may howeverbe the case that no excipient is needed at all for soft gelatinecapsules.

[0290] For the preparation of solutions and syrups, excipients which maybe used include for example water, polyols, saccharose, invert sugar andglucose.

[0291] For injectable solutions, excipients which may be used includefor example water, alcohols, polyols, glycerine, and vegetable oils.

[0292] For suppositories, and local or percutaneous application,excipients which may be used include for example natural or hardenedoils, waxes, fats and semi-solid or liquid polyols.

[0293] The pharmaceutical compositions may also contain preservingagents, solubilising agents, stabilising agents, wetting agents,emulsifiers, sweeteners, colorants, odorants, salts for the variation ofosmotic pressure, buffers, coating agents or antioxidants. As mentionedearlier, they may also contain other therapeutically valuable agents.

[0294] It is a prerequisite that all adjuvants used in the manufactureof the preparations are non-toxic.

[0295] Intravenous, intramuscular or oral administration is a preferredform of use. The dosages in which the compounds of formula (I) areadministered in effective amounts depend on the nature of the specificactive ingredient, the age and the requirements of the patient and themode of application. In general, daily dosages of about 1 mg -1000 mg,preferably 5 mg -500 mg, per day come into consideration.

[0296] The following Examples shall illustrate preferred embodiments ofthe present invention but are not intended to limit the scope of theinvention.

[0297] The corresponding starting materials are either commerciallyavailable or can be obtained by methods known in the art (e.g. from: DE26 24 290; WO 98/0354; Chem. Pharm. Bull., 38(2), 350-354 (1990), ChiralSynthon Obtained with Pig Liver Esterase: Introduction of Chiral Centersinto Cyclohexene Skeleton; J. Chem. Soc. Perkin Trans., 1, 1411-1415(1994), Asymmetric Synthesis of (−)-(1R,2S)-Cispentacin and Related cis-and trans-2-Amino Cyclopentane- and Cyclohexane-1-carboxylic Acids) orcan be obtained by methods analogous to the methods described before.

EXAMPLE 1

[0298] Preparation of (R,S)-α-amino-3-bromophenylacetonitrile

[0299] NH₄Cl (2.14 g, 40 mmol) and NaCN (1.96 g, 40 mmol) are dissolvedin 20 ml H₂O and 20 ml MeOH and cooled to 0° C. A solution of3-bromobenzaldehyde (4.68 ml, 40 mmol) in 15 ml CH₂Cl₂ and 15 MeOH isadded dropwise over 30 min. The mixture is allowed to warm to RT andstirred for 0.5 h. NH₃ solution (25% in H₂O) (6 ml, 80 mmol) is added.The mixture is stirred for 16 h at RT. The organic solvents areevaporated and H₂O is added (5 to 10 ml). The water layer is extractedwith CH₂Cl₂ (2×50 ml) and the latter is washed with H₂O (20 ml) andbrine (20 ml), dried over Na₂SO₄ and evaporated. The oily residue isdissolved in 75 ml ether. While stirring vigorously dropwise a 4 M HClsolution in dioxane is added. A solid precipitates and is filtered anddried. To recrystallize the solid is dissolved in as little MeOH aspossible (do not heat!). Now, while stirring, ether is added untilprecipitation has finished. The precipitate is filtered and dried invacuo.

[0300] Yield: 40% MS: 229 (MNH4+)

EXAMPLE 2

[0301] Preparation of chiral amino nitriles:

[0302] (S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester

[0303] 0.628 g (7.95 mmol, 1 eq) ammonium bicarbonate is added to themixed anhydride (prepared from 7.95 mmol (S)-BOC-phenyl glycine and 10.4mmol di-tert-butyl dicarbonate in 40 ml dioxane and 2.39 mmol pyridine)at 15 ° C. The mixture is stirred for 8 h at this temperature andconcentrated. The residue is dissolved in 20 ml ethyl acetate, washedwith saturated sodium bicarbonate, 2N HCL, brine, dried over sodiumsulfate and evaporated.

[0304] Yield: 92%, MS: 251 (MH+), [α]_(D) ²⁵=−120.4 (1.00, EtOH)

[0305] (R)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester isprepared analogously to (S)-(Carbamoyl-phenyl-methyl)-carbamic acidtert-butyl ester.

[0306] Preparation of (S)-(Cyano-phenyl-methyl)-carbamic acid tert-butylester

[0307] (S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester (1.8g, 7.19 mmol) and triethylamine (2.2 ml, 15.8 mmol) are dissolved in THF(40 ml) at −10 ° C. Trifluoroacetic acid anhydride (1.1 ml, 7.91 mmol)is added over 30 min. The mixture is stirred at −10 ° C. for 2 h andevaporated. Dichloromethane and water are added. The organic phase isseparated, dried over sodium sulfate and evaporated. The crude productis purified by chromatography (silica gel, ethyl acetate/hexane=4:1,R=0.5).

[0308] Yield: 81%, MS: 231 (M−H)⁻, [α]_(D) ²⁵=+4.1 (1.00, EtOH)

[0309] (R)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester isprepared analogously to (S)-(Cyano-phenyl-methyl)-carbamic acidtert-butyl ester.

[0310] Preparation of (S)-Amino-phenyl-acetonitrile hydrochloride

[0311] (S)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester (0.5 g,2.15 mmol) is dissolved in 5 ml HCl/abs. AcOH (10%). The mixture isstirred at RT for 2 h and evaporated. The product is washed with dietylether and dried in vacuo.

[0312] Yield: 98%, MS: 192 (M+Na)⁺, [α]_(D) ²⁵=+38.6 (1.00, water)

[0313] (R)-Amino-phenyl-acetonitrile hydrochloride is preparedanalogously to (S)-Amino-phenyl-acetonitrile hydrochloride.

EXAMPLE 3

[0314] Preparation of cis-(2-f (R)- and(S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyll-cyclohexyl)-carbamicacid benzyl ester

[0315] A solution of 0.7mmol cis-2-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (educt 1), 5.2 mmol N-methylmorpholin, 0.15 mmol HOBTand 1.78 mmol EDCI in 12 ml CH₂Cl₂ is added to 0.97 mmolAmino-(3,4-dimethoxy-phenyl)-acetonitrile; hydrochloride (educt 2).After shaking overnight the reaction mixture is extracted with 10 ml 1 NHCl and the CH₂Cl₂ is evaporated. The compound is purified by HPLC:

[0316] column: HP-CombiHT XDB-C18, 21.2 mmI.D.×50 mm, Series No DN 1020

[0317] method: Flow: 40 ml/min

[0318] 0 min 80% water, 20% acetonitrile

[0319] 0.2 min 80% water, 20% acetonitrile

[0320] 3.5 min 5% water, 95% acetonitrile

[0321] 4.7 min 5% water, 95% acetonitrile

[0322] 4.8 min 80% water, 20% acetonitrile

[0323] 4.9 min 80% water, 20% acetonitrile

[0324] machine: Prep HPLC System Dynamax Model SD-1, UV-1

[0325] Yield: 59%, MS: 452(MH+)

EXAMPLE 4

[0326] Preparation of (1S,2R)-{2-(R)- and(S)-[(Cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester

[0327] A solution of 0.18 mmol(1S,2R)-2-Benzyloxycarbonylamino-cyclohexane carboxylic acid (educt 1),0.72 mmol N-ethyldiisopropylamine and 0.18 mmol TPTU in 10 mlacetonitrile is added to 0.18 mmol Amino-phenyl-acetonitrilehydrochloride (educt 2). After stirring overnight the solvent isevaporated. The residue is dissolved in ethyl acetate, extracted withsodium hydrogencarbonate solution (3×) and brine. The solution is driedover sodium sulfate and evaporated. The compound is purified by flashchromatography (silicagel, ethyl acetate/hexane 7:3).

[0328] Yield: 83%, MS: 390(M−H)

EXAMPLE 5

[0329] Preparation oftrans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid

[0330] Trans-2-Aminocyclohexanecarboxylic acid ( 0.150 g, 1.05 mmol) isdissolved in 1.5 ml of water and NaOH (0.09 g, 2.25 mmol) in 1.5 ml ofwater is added at 0° C. 4-Chlorobenzene sulfonyl chloride (0.243 g, 1.15mmol) in 1.5 ml of toluene is added. The reaction mixture is stirred atroom temperature for 16 hours. The toluene layer is separated and theaqueous layer is washed twice with toluene. The toluene layers arediscarded. Ethyl acetate is added to the aqueous layer (15 ml) and 2MHCl until pH<7. The two phases are separated and the aqueous layer isextracted with ethyl acetate (3×15 mL). The combined organic phases arewashed with brine (20 ml), dried over MgSO₄ and the ethyl acetate isremoved under reduced pressure leaving a white solid that is dissolvedin toluene (2×10 ml) and concentrated The product is dried in vacuum.

[0331] Yield: 70%, MS: 316 (M−H).

[0332] Preparation oftrans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide

[0333] Trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylicacid (0.095 g, 0.3 mmol) is dissolved in CH₃CN.O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TPTU, 90.2 mg, 0.3 mmol), N-Ethyldiisopropylamine(DIPEA, 0.208 ml, 1.21 mmol) are added. Theamino-(3-hydroxy-phenyl)-acetonitrile in CH₃CN (1.5 ml) is added. Themixture is stirred at RT for 16 hours. The solution is filtered andconcentrated. The residue is dissolved in CH₂Cl₂ (15 mL) and extractedwith NH₄Cl (2×10 ml). The H₂O layers are extracted with CH₂Cl₂ (2×15ml). The collected CH₂Cl₂ layers are dried over MgSO₄ and evaporated.The solid is purified by preparative HPLC.

[0334] column: YMC; CombiPrep ODS_AQ; 50*20 mml.D; S-5 um, 120A

[0335] method: Flow: 40 ml/min

[0336] Omin 90% water, 10% acetonitrile

[0337] 0.1 L 90% water, 10% acetonitrile

[0338] 3.5 min 5% water, 95% acetonitrile

[0339] 5.5 min 5% water, 95% acetonitrile

[0340] 5.7 min 80% water, 20% acetonitrile

[0341] 5.8 min 80% water, 20% acetonitrile

[0342] machine: Prep HPLC System Dynamax Model SD-1, UV-1.

[0343] Yield: 26%, MS: 470(MNa+)

EXAMPLE 6

[0344] Preparation of Carbonic acid 4-nitro-phenyl esterthiophen-2-ylmethyl ester

[0345] To a solution of the Thiophen-2-yl-methanol (0.412 g, 3.6 mmol)in CH₂Cl₂ (6 ml) is added pyridine (0.291 ml, 3.6 mmol) and4-Nitrophenylchloroformate (0.728 g, 3.6 mmol) at 0° C. After shakingovernight, the reaction mixture is extracted with NH₄Cl (5 ml) and theCH₂Cl₂ is evaporated leaving a white solid which is used without furtherpurification.

[0346] Preparation ofcis-2-(Thiophen-2-ylmethoxycarbonylamino)-cyclohexanecarboxylic acid

[0347] To a solution of Trans-2-amino-1-cyclohexane carboxylic acid (100mg, 0.7 mmol) in lmL of water is added 2M aqueous Na₂CO₃ until pH=9-10(2 mL). A solution of the carbonic acid 4-nitro-phenyl esterthiophen-2-ylmethyl ester (195 mg, 0.7 mmol) in THF (1 mL) is added at0° C. and, after 10 minutes, 1 ml of the 2M Na₂CO₃ is added to thereaction. The mixture is allowed to warm to RT and vigorously stirredovernight. The reaction mixture is diluted with 0.5N HCl until pH=4-3and the water layer is extracted three times with CH₂Cl₂ (10 ml). Theorganic phases are combined, dried (MgSO₄), and concentrated underreduced pressure. The resulting product is used in the next step withoutfurther purification.

[0348] Yield 68% MS: 282 (M−H)

[0349] Preparation oftrans-(2-{[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-2-ylmethyl ester

[0350]Trans-(2-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-2-ylmethyl ester (0.094 g, 0.33 mmol) is dissolved in DMF(1 ml). O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TPTU, 0.099 mg, 0.33 mmol) andN-Ethyldiisopropylamine (DIPEA, 0.228 ml, 1.32 mmol) are added. Theamino -(3-hydroxy-phenyl)-acetonitrile in DMF (1.5 ml) is added and themixture is stirred overnight at RT. The reaction mixture is filtered andthe product is obtained by HPLC.

[0351] column: YMC; CombiPrep ODS_AQ; 50*20 mml.D; S-5 um, 120A

[0352] method: Flow: 40 ml/min

[0353] 0 min 90% water, 10% acetonitrile

[0354] 0.1 L 90% water, 10% acetonitrile

[0355] 3.5 min 5% water, 95% acetonitrile

[0356] 5.5 min 5% water, 95% acetonitrile

[0357] 5.7 min 80% water, 20% acetonitrile

[0358] 5.8 min 80% water, 20% acetonitrile

[0359] machine: Prep HPLC System Dynamax Model SD-1, UV-1.

[0360] Yield 24%, MS: 436(MNa+)

EXAMPLE 7

[0361] Preparation of 2-Amino-cyclohexanecarboxylic acid[cyano-(3,4-dimethoxy-phenyl)-methyl]-amide; compound withtrifluoro-acetic acid

[0362] To a solution of 15.7 mmol2-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid, 17.2 mmol (R,S)-Amino-(3,4-dimethoxy-phenyl)-acetonitrile; hydrochloride, 1.57 mmol HOBTand 18.8 mmol EDCI in 150 ml CH₂Cl₂ is added 109.7 mmolN-methylmorpholine. After stirring overnight at RT the reaction mixtureis extracted with 150 ml 10% KHSO₄ and 150 ml sat. NaHCO₃, dried overMgSO₄, evaporated and purified by flash chromatography (4 cm Glassfrit,2cm silicagel 0.04-0.063, eluent 400 ml CH₂Cl₂). BOC-cleavage isperformed with 17 ml TFA in 50 ml CH₂Cl₂ within 4 hours at RT.Evaporation yields a brown oil which is used without furtherpurification.

[0363] Preparation ofcis-2-(3-Phenyl-acryloylamino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide

[0364] To a solution of 0.17 mmol cis-2-Amino-cyclohexanecarboxylic acid[cyano-(3,4-dimethoxy-phenyl)-methyl]-amide; compound withtrifluoro-acetic acid (educt 1) in 3 ml CH₂Cl₂ is added a solution of0.187 mmol trans-Cinnamoyl cholride (educt 2) in 1 ml CH₂Cl₂. To thismixture is added 0.36 mmol triethylamine. After shaking overnight at RTformic acid is added, the CH₂Cl₂ is evaporated and the compound purifiedby HPLC:

[0365] column: HP-CombiHT XDB-C18, 21.2 mmI.D.×50 mm, Series No DN 1020

[0366] method: Flow: 40 ml/min

[0367] 0 min 80% water, 20% acetonitrile

[0368] 0.2 min 80% water, 20% acetonitrile

[0369] 3.5 min 5% water, 95% acetonitrile

[0370] 4.7 min 5% water, 95% acetonitrile

[0371] 4.8 min 80% water, 20% acetonitrile

[0372] 4.9 min 80% water, 20% acetonitrile

[0373] machine: Prep HPLC System Dynamax Model SD-1, UV-1

[0374] Yield: 19%, MS: 448 (MH+)

EXAMPLE 8

[0375] Preparation of other compounds of formula (I)

[0376] Several additional compounds of formula (I) have been prepared.The following table shows an overview of the products, the educts andthe method used for the preparation. No. Compound Method Educt 1 Educt 2MW MS 1 (1R,2R)-(2-{(S)-[Cyano-(3-hydroxy- A-2 (1R,2R)-trans-2-2-Amino-2-(3- 407.47 408 (MH+) phenyl)-methyl]-carbamoyl}-Benzyloxycarbonylamino- hydroxyphenyl) cyclohexyl)-carbamic acid benzylester cyclohexane carboxylic acid acetonitrile 2cis-2-(3-Phenyl-acryloylamino)- B cis-2-Amino-cyclohexanecarboxylictrans-Cinnamoyl 447.53 448 (MH+) cyclohexanecarboxylic acid [(R)-andacid [cyano-(3,4-dimethoxy-phenyl)- chloride(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 3 (R)-{2-[(S)-(Cyano-phenyl-methyl)-A-2 (1R,2R)-trans-2- (S)-Amino-phenyl- 391.47 409 (MNH4+)(R)-carbamoyl]-cyclohexyl}-carbamic Benzyloxycarbonylamino-acetonitrile; acid benzyl ester cyclohexane carboxylic acidhydrochloride 4 syn-{2-[(S)-(Cyano-phenyl-methyl)- A-2cis-2-Benzyloxycarbonylamino- (S)-Amino-phenyl- 391.47 409 (MNH4+)carbamoyl]-cyclohexyl}-carbamic acid cyclohexane carboxylic acidacetonitrile; benzyl ester hydrochloride 5cis-(2-{(R)-and(S)-[Cyano-(2,4- A cis-2-Benzyloxycarbonylamino-Amino-(3,4- 451.52 452 (MH+) dimethoxy-phenyl)-methyl]- cyclohexanecarboxylic acid dimethoxy-phenyl)- carbamoyl}-cyclohexyl)-carbamic acidacetonitrile; benzyl ester hydrochloride 6 trans-2-(4-Chloro- Ctrans-2-(4-Chloro- Amino-(3-hydroxy- 447.94 470 (MNa+)benzenesulfonylamino)- benzenesulfonylamino)- phenyl)-acetonitrilecyclohexanecarboxylic acid [cyano-(3- cyclohexanecarboxylic acidhydroxy-phenyl)-methyl]-amide 7 trans-{2-[(Benzo[1,3]dioxol-5-yl- A-2trans-2-Benzyloxycarbonylamino- Amino- 435.48 436 (MH+)cyano-methyl)-carbamoyl]-cyclohexyl}- cyclohexane carboxylic acidbenzo[1,3]dioxol-5- carbamic acid benzyl ester yl-acetonitrile;hydrochloride 8 cis-(2-{[Cyano-(3-hydroxy-phenyl)- A-2cis-2-Benzyloxycarbonylamino- 2-Amino-2-(3- 407.47 425 (MNH4+)methyl]-carbamoyl}-cyclohexyl)- cyclohexane carboxylic acidhydroxyphenyl) carbamic acid benzyl ester acetonitrile 9trans-(2-{[Cyano-(3-hydroxy-phenyl)- A-2 trans-2-Benzyloxycarbonylamino-2-Amino-2-(3- 407.47 425 (MNH4+) methyl]-carbamoyl}-cyclohexyl)-cyclohexane carboxylic acid hydroxyphenyl) carbamic acid benzyl esteracetonitrile 10 cis-2-(3-Phenyl-acryloylamino- Bcis-2-Amino-cyclohexanecarboxylic trans-Cinnamoyl 387.48 487 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;cholride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 11 (2-{[Cyano-(3,4-dimethoxy-phenyl)- A-2cis-2-Benzyloxycarbonylamino- Amino-(3,4- 451.53 474 (MNa+)methyl]-carbamoyl}-cyclohexyl)- cyclohexane carboxylic aciddimethoxy-phenyl)- carbamic acid benzyl ester (1 cis- acetonitrile;racemate) hydrochloride 12 cis-{2-[(R)- and (S)-(Cyano-m-tolyl- Acis-2-Benzyloxycarbonylamino- Amino-m-tolyl- 405.5 406 (MH+)methyl)-carbamoyl]-cyclohexyl}- cyclohexane carboxylic acidacetonitrile; carbamic acid benzyl ester hydrochloride 13(2-{[Cyano-(3-hydroxy-phenyl)- D cis-2-(Thiophen-3- 2-Amino-2-(3- 413.5436 (MNa+) methyl]-carbamoyl}-cyclohexyl)- ylmethoxycarbonylamino)-hydroxyphenyl) carbamic acid thiophen-3-ylmethyl estercyclohexanecarboxylic acid acetonitrile 14 cis-(2-{(R)- and(S)-[Cyano-(4- A cis-2-Benzyloxycarbonylamino- Amino-(4-methoxy- 421.49394 (MNa+) methoxy-phenyl)-methyl]-carbamoyl}- cyclohexane carboxylicacid phenyl)-acetonitrile; cyclohexyl)-carbamic acid benzyl esterhydrochloride 15 cis-(2-{(R)- and (S)-[Cyano-(3- Acis-2-Benzyloxycarbonylamino- Amino-(3-methoxy- 421.49 444 (MNa+)methoxy-phenyl)-methyl]-carbamoyl}- cyclohexane carboxylic acidphenyl)-acetonitrile; cyclohexyl)-carbamic acid benzyl esterhydrochloride 16 trans-(2-{[Cyano-(3-hydroxy-phenyl)- Dtrans-2-(Thiophen-2- 2-Amino-2-(3- 413.5 436 (MNa+)methyl]-carbamoyl}-cyclohexyl)- ylmethoxycarbonylamino)- hydroxyphenyl)carbamic acid thiophen-2-ylmethyl ester cyclohexanecarboxylic acidacetonitrile 17 cis-(2-{(R)- and (S)-[(3-Chloro- Acis-2-Benzyloxycarbonylamino- Amino-(3-chloro- 425.91 448 (MNa+)phenyl)-cyano-methyl]-carbamoyl}- cyclohexane carboxylic acidphenyl)-acetonitrile cyclohexyl)-carbamic acid benzyl esterhydrochloride 18 cis-{2-[(Cyano-phenyl-methyl)- A-2cis-2-Benzyloxycarbonylamino- Amino-phenyl- 391.47 414 (MNa+)carbamoyl]-cyclohexyl}-carbamic acid cyclohexane carboxylic acidacetonitrile; benzyl ester hydrochloride 19trans-(2-{[(3-Bromo-phenyl)-cyano- A-2 cis-2-Benzyloxycarbonylamino-Amino-(3-bromo- 470.38 493 (MNa+) methyl]-carbamoyl}-cyclohexyl)-cyclohexane carboxylic acid phenyl)-acetonitrile carbamic acid benzylester hydrochloride 20 cis-(2-{(R)- and (S)-[(4-Bromo- Acis-2-Benzyloxycarbonylamino- Amino-(4-bromo- 470.37 470 (MH+)phenyl)-cyano-methyl]-carbamoyl}- cyclohexane carboxylic acidphenyl)-acetonitrile cyclohexyl)-carbamic acid benzyl esterhydrochloride 21 cis-(2-{[(R)- and (S)-Cyano-(3,4- Bcis-2-Amino-cyclohexanecarboxylic Cyclopentyl 429.51 430 (MH+)dimethoxy-phenyl)-methyl]- acid [cyano-(3,4-dimethoxy-phenyl)-chloroformate carbamoyl}-cyclohexyl)-carbamic acid methyl]-amide;compound with cyclopentyl ester trifluoro-acetic acid 22trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans2-(2-Thiophen-2-yl-2-Amino-2-(3- 427.52 428 (MH+) methyl]-carbamoyl}-cyclohexyl)-ethoxycarbonylamino)- hydroxyphenyl) carbamic acid 2-thiophen-2-yl-ethylcyclohexanecarboxylic acid acetonitrile ester 23trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(2-Methyl- 2-Amino-2-(3-421.49 444 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 2-methyl-benzylester cyclohexanecarboxylic acid acetonitrile 24trans-2-Phenylmethanesulfonylamino- C trans-2- Amino-(3-hydroxy- 427.52428 (MH+); cyclohexanecarboxylic acid [cyano-(3-Phenylmethanesulfonylamino- phenyl)-acetonitrile 450 (M + Na)hydroxy-phenyl)-methyl]-amide cyclohexanecarboxylic acid 25trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(2-Chloro- 2-Amino-2-(3-441.91 464 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 2-chloro-benzylester cyclohexanecarboxylic acid acetonitrile 26 cis-(2-{(R)- and(S)-[(4-Chloro- A cis-2-Benzyloxycarbonylamino- Amino-(3-chloro- 441.91464 (MNa+) phenyl)-cyano-methyl]-carbamoyl}- cyclohexane carboxylic acidphenyl)-acetonitrile cyclohexyl)-carbamic acid benzyl esterhydrochloride 27 (2-{[Cyano-(3-hydroxy-phenyl)- D 2-(4-Fluoro-2-Amino-2-(3- 425.46 448 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 4-fluoro-benzylester cyclohexanecarboxylic acid acetonitrile 28 cis-{2-[(R)- and(S)-(Cyano-phenyl- B cis-2-Amino-cyclohexanecarboxylic Chloroformic acid2- 427.5 428 (MH+) methyl-carbamoyl]-cyclohexyl}- acid(cyano-phenyl-methyl)-amide; naphthyl ester carbamic acid napthalen-2-ylester compound with trifluoro-acetic acid 29 cis-{2-[(R)- and(S)-(Cyano- A cis-2-Benzyloxycarbonylamino- Amino-naphthalen-2- 441.53442 (MH+) naphthalen-2-yl-methyl)-carbamoyl]- cyclohexane carboxylicacid yl-acetonitrile; cyclohexyl}-carbamic acid benzyl esterhydrochloride 30 trans-(2-{[Cyano-(3-hydroxy-phenyl)- Dtrans-2-(3-Thiophen-2-yl- 2-Amino-2-(3- 413.5 436 (MNa+)methyl]-carbamoyl}-cyclohexyl)- propoxycarbonylamino)- hydroxyphenyl)carbamic acid 3-thiophen-2-yl-propyl cyclohexanecarboxylic acidacetonitrile ester 31 trans-2-(4-Cyano- C trans-2-(4-Cyano-Amino-(3-hydroxy- 438.51 461 (MNa+) benzenesulfonylamino)-benzenesulfonylamino)- phenyl)-acetonitrile cyclohexanecarboxylic acid[cyano-(3- cyclohexanecarboxylic acid hydroxy-phenyl)-methyl]-amide 32trans-(2-{[(3-Bromo-phenyl)-cyano- A-2 trans-2-Benzyloxycarbonylamino-Amino-(3-bromo- 470.38 493 (MNa+) methyl]-carbamoyl}-cyclohexyl)-cyclohexane carboxylic acid phenyl)-acetonitrile carbamic acid benzylester hydrochloride 33 cis-Acetic acid 4-(R)- and (S)-[(2- Acis-2-Benzyloxycarbonylamino- Acetic acid 4-(amino- 449.5 394 (MNa+)benzyloxycarbonylamino- cyclohexane carboxylic acid cyano-methyl)-phenylcyclohexanecarbonyl)-amino]-cyano- ester; hydrochloride methyl}-phenylester 34 trans-{2-[(Cyano-phenyl-methyl)- A-2trans-2-Benzyloxycarbonylamino- Amino-phenyl- 391.47 414 (MNa+)carbamoyl]-cyclohexyl}-carbamic acid cyclohexane carboxylic acidacetonitrile; benzyl ester hydrochloride 35 cis-N-(2-{[(R)- and(S)-Cyano-(3,4- B cis-2-Amino-cyclohexanecarboxylic Benzoic acidchloride 421.49 422 (MH+) dimethoxy-phenyl)-methyl]- acid[cyano-(3,4-dimethoxy-phenyl)- carbamoyl}-cyclohexyl)-benzamidemethyl]-amide; compound with trifluoro-acetic acid 36trans-(2-{[(3-Bromo-4-methoxy- A-2 trans-2-Benzyloxycarbonylamino-Amino-(3-bromo-4- 500.4 519 (MNH4+) phenyl)-cyano-methyl]-carbamoyl}-cyclohexane carboxylic acid methoxy-phenyl)- cyclohexyl)-carbamic acidbenzyl ester acetonitrile; hydrochloride 37 cis-{2-[(R)- and (S)-(Cyano-A cis-2-Benzyloxycarbonylamino- Amino-naphthalen-1- 441.53 464 (MNa+)naphthalen-1-yl-methyl)-carbamoyl]- cyclohexane carboxylic acidyl-acetonitrile; cyclohexyl}-carbamic acid benzyl ester hydrochloride 38trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(2-Methoxy- 2-Amino-2-(3-437.49 460 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 2-methoxy-benzylester cyclohexanecarboxylic acid acetonitrile 39(1R,2R)-(2-{(R)-[Cyano-(3-hydroxy- A-2 (R,R)-2-Benzyloxycarbonylamino-2-Amino-2-(3- 407.47 408 (MH+) phenyl)-methyl]-carbamoyl}- cyclohexanecarboxylic acid hydroxyphenyl) cyclohexyl)-carbamic acid benzyl esteracetonitrile 40 trans-(2-{[(3-Bromo-4-methoxy- A-2trans-2-Benzyloxycarbonylamino- Amino-(3-bromo-4- 500.4 519 (MNH4+)phenyl)-cyano-methyl]-carbamoyl}- cyclohexane carboxylic acidmethoxy-phenyl)- cyclohexyl)-carbamic acid benzyl ester acetonitrile;hydrochloride 41 trans-[2-(Cyanomethyl-carbamoyl)- A-2trans-2-Benzyloxycarbonylamino- Acetaminoacetonitrile 315.38 316 (MH+)cyclohexyl]-carbamic acid benzyl ester cyclohexane carboxylic acidbisulfate 42 trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(3-Chloro-2-Amino-2-(3- 441.91 464 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 3-chloro-benzylester cyclohexanecarboxylic acid acetonitrile 43trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(3-Methyl- 2-Amino-2-(3-421.49 444 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 3-methyl-benzylester cyclohexanecarboxylic acid acetonitrile 44cis-Biphenyl-4-carboxylic acid (2-{[(R)- Bcis-2-Amino-cyclohexanecarboxylic 4-Biphenylcarbonyl 497.59 498 (MH+)and (S)-cyano-(3,4-dimethoxy-phenyl)- acid[cyano-(3,4-dimethoxy-phenyl)- chloridemethyl]-carbamoyl}-cyclohexyl)-amide methyl]-amide; compound withtrifluoro-acetic acid 45 cis-{2-[(R)- and (S)-(Cyano-phenyl- Bcis-2-Amino-cyclohexanecarboxylic Phenyl chloroformate 377.44 378 (MH+)methyl-carbamoyl]-cyclohexyl}- acid (cyano-phenyl-methyl)-amide;carbamic acid phenyl ester compound with trifluoro-acetic acid 46trans-2-(4-Acetylamino- C trans-2-(4-Acetylamino- Amino-(3-hydroxy-470.55 493 (MNa+) benzenesulfonylamino)- benzenesulfonylamino)-phenyl)-acetonitrile cyclohexanecarboxylic acid [cyano-(3-cyclohexanecarboxylic acid hydroxy-phenyl)-methyl]-amide 47cis-N-{2-[(R)- and (S)-(Cyano-phenyl- Bcis-2-Amino-cyclohexanecarboxylic Benzoic acid chloride 361.44 362 (MH+)methyl-carbamoyl]-cyclohexyl}- acid (cyano-phenyl-methyl)-amide;benzamide compound with trifluoro-acetic acid 48trans-2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(3-Methoxy- 2-Amino-2-(3-437.49 460 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 3-methoxy-benzylester cyclohexanecarboxylic acid acetonitrile 49trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(4-Methyl- 2-Amino-2-(3-421.49 441 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 4-methyl-benzylester cyclohexanecarboxylic acid acetonitrile 50cis-{2-[(Benzo[1,3]dioxol-5-yl-cyano- A-2 cis-2-Benzyloxycarbonylamino-Amino- 435.48 453 (MNH4+) methyl)-carbamoyl]-cyclohexyl}- cyclohexanecarboxylic acid benzo[1,3]dioxol-5- carbamic acid benzyl esteryl-acetonitrile; hydrochloride 51 trans-4-Cyano-N-(2-{[cyano-(3- Ctrans-2-(4-Cyano-benzoylamino)- Amino-(3-hydroxy- 402.45 425 (MNa+)hydroxy-phenyl)-methyl]-carbamoyl}- cyclohexanecarboxylic acidphenyl)-acetonitrile cyclohexyl)-benzamide 52trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(4-Methoxy- 2-Amino-2-(3-437.49 460 (MNa+) methyl]-carbamoyl}-cyclohexyl)-benzyloxycarbonylamino)- hydroxyphenyl) carbamic acid 4-methoxy-benzylester cyclohexanecarboxylic acid acetonitrile 53cis-2-(3-Cyclopentyl-propionylamino)- Bcis-2-Amino-cyclohexanecarboxylic Cyclopentyl-propionyl 441.57 442 (MH+)cyclohexanecarboxylic acid [(R)- and acid [cyano-(3,4-dimethoxy-phenyl)-chloride (S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 54(2-{[Cyano-(3,4-dimethoxy-phenyl)- A-2 cis-2-Benzyloxycarbonylamino-Amino-(3,4- 451.53 474 (MNa+) methyl]-carbamoyl}-cyclohexyl)-cyclohexane carboxylic acid dimethoxy-phenyl)- carbamic acid benzylester (1 cis- acetonitrile; racemate) hydrochloride 55 cis-{2-[(R)- and(S)-(Cyano-phenyl- B cis-2-Amino-cyclohexanecarboxylic 4-Nitrobenzyl436.47 437 (MH+) methyl-carbamoyl]-cyclohexyl}- acid(cyano-phenyl-methyl)-amide; chloroformate carbamic acid 4-nitro-benzylester compound with trifluoro-acetic acid 56 cis-(2-{[(R)- and(S)-Cyano-(3,4- B cis-2-Amino-cyclohexanecarboxylic 4-Nitrobenzyl 496.52497 (MH+) dimethoxy-phenyl)-methyl]- acid [cyano-(3,4-dimethoxy-phenyl)-chloroformate carbamoyl}-cyclohexyl)-carbamic acid methyl]-amide;compound with 4-nitro-benzyl ester trifluoro-acetic acid 57cis-2-(3-Phenyl-propionylamino)- B cis-2-Amino-cyclohexanecarboxylic3-Phenylpropionyl 449.55 450 (MH+) cyclohexanecarboxylic acid [(R)- andacid [cyano-(3,4-dimethoxy-phenyl)- chloride(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 58cis-2-(Cyclopropanecarbonyl-amino)- B cis-2-Amino-cyclohexanecarboxylicCyclopropanecarbonyl 385.46 386 (MH+) cyclohexanecarboxylic acid [(R)-and acid [cyano-(3,4-dimethoxy-phenyl)- chloride(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 59 cis-{2-[(R)- and(S)-(Cyano-phenyl- B cis-2-Amino-cyclohexanecarboxylic Cyclopentyl369.46 370 (MH+) methyl-carbamoyl]-cyclohexyl}- acid(cyano-phenyl-methyl)-amide; chloroformate carbamic acid cyclopentylester compound with trifluoro-acetic acid 60trans-(2-{[Cyano-(3-hydroxy-phenyl)- D trans-2-(3-p-Tolyl- 2-Amino-2-(3-449.55 472 (MNa+) methyl]-carbamoyl}-cyclohexyl)- propoxycarbonylamino)-hydroxyphenyl) carbamic acid 3-p-tolyl-propyl estercyclohexanecarboxylic acid acetonitrile 61 cis-[2-((R)- and(S)-1-Cyano-3-methyl- A cis-2-Benzyloxycarbonylamino- 2-Amino-4-methyl-371.48 394 (MNa+) butylcarbamoyl)-cyclohexyl]-carbamic cyclohexanecarboxylic acid pentanenitrile; acid benzyl ester hydrochloride 62cis-2-(2-Phenoxy-acetylamino)- B cis-2-Amino-cyclohexanecarboxylicPhenoxyacetyl 451.52 452 (MH+) cyclohexanecarboxylic acid [(R)- and acid[cyano-(3,4-dimethoxy-phenyl)- chloride(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 63 trans-2-(2-Phenoxy-acetylamino)-C trans-2-(2-Phenoxy-acetylamino)- Amino-(3-hydroxy- 407.47 408 (MH+)cyclohexanecarboxylic acid [cyano-(3- cyclohexanecarboxylic acidphenyl)-acetonitrile hydroxy-phenyl)-methyl]-amide 64 cis-(2-{(R)- and(S)-[Cyano-(2,4- A cis-2-Benzyloxycarbonylamino- Amino-(2,4-dimethyl-419.52 420 (MH+) dimethyl-phenyl)-methyl]-carbamoyl}- cyclohexanecarboxylic acid phenyl)-acetonitrile; cyclohexyl)-carbamic acid benzylester hydrochloride 65 cis-2-[2-(4-Chloro-phenoxy)- Bcis-2-Amino-cyclohexanecarboxylic 4- 485.97 486 (MH+)acetylamino]-cyclohexanecarboxylic acid [cyano-(3,4-dimethoxy-phenyl)-Chlorophenoxyacetyl acid [(R)- and (S)-cyano-(3,4- methyl]-amide;compound with chloride dimethoxy-phenyl)-methyl]-amide trifluoro-aceticacid 67 cis-2-(2-Phenylsulfanyl-acetylamino- Bcis-2-Amino-cyclohexanecarboxylic (Phenylthio)acetyl 407.54 408 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;choride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 68 trans-(2-{[Cyano-(3-hydroxy-phenyl)- Dtrans-2-[3-(4-Chloro-phenyl)- 2-Amino-2-(3- 469.97 470 (MH+)methyl]-carbamoyl}-cyclohexyl)- propoxycarbonylamino]- hydroxyphenyl)carbamic acid 3-(4-chloro-phenyl)- cyclohexanecarboxylic acidacetonitrile propyl ester 69 cis-2-(2-Phenylsulfanyl-acetylamino)- Bcis-2-Amino-cyclohexanecarboxylic (Phenylthio)acetyl 467.59 468 (MH+)cyclohexanecarboxylic acid [(R)- and acid [cyano-(3,4-dimethoxy-phenyl)-choride (S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 70trans-2-(Benzo[1,2,5]oxadiazole-4- C trans-2-(Benzo[1,2,5]oxadiazole-4-Amino-(3-hydroxy- 455.49 478 (MNa+) sulfonylamino)-cyclohexanecarboxylicsulfonylamino)- phenyl)-acetonitrile acid [cyano-(3-hydroxy-phenyl)-cyclohexanecarboxylic acid methyl]-amide 71trans-N-(2-{[Cyano-(3-hydroxy- C trans-2-(4-Fluoro-benzoylamino)-Amino-(3-hydroxy- 395.43 396 (MH+) phenyl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid phenyl)-acetonitrilecyclohexyl)-4-fluoro-benzamide 72 cis-2-[2-(4-Chloro-phenoxy- Bcis-2-Amino-cyclohexanecarboxylic 4- 425.91 426 (MH+)acetylamino]-cyclohexanecarboxylic acid (cyano-phenyl-methyl)-amide;Chlorophenoxyacetyl acid ((R)- and (S)-cyano-phenyl- compound withtrifluoro-acetic acid chloride methyl-amide 73cis-2-(3-Phenyl-propionylamino)- A-2 cis-2-Benzyloxycarbonylamino-Amino-phenyl- 389.5 390 (MH+) cyclohexanecarboxylic acid (cyano-cyclohexane carboxylic acid acetonitrile; phenyl-methyl)-amidehydrochloride 74 cis-2-Phenylacetylamino- Bcis-2-Amino-cyclohexanecarboxylic Phenylacetyl chloride 435.52 436 (MH+)cyclohexanecarboxylic acid [(R)- and acid [cyano-(3,4-dimethoxy-phenyl)-(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 75 cis-2-Phenylmethanesulfonylamino-B cis-2-Amino-cyclohexanecarboxylic alpha- 471.58 489 (MNH4+)cyclohexanecarboxylic acid [(R)- and acid [cyano-(3,4-dimethoxy-phenyl)-Toluenesulphonyl (S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide;compound with chloride methyl]-amide trifluoro-acetic acid 76trans-2-(2-Phenylsulfanyl- C trans-2-(2-Phenylsulfanyl-Amino-(3-hydroxy- 423.53 424 (MH+) acetylamino)-cyclohexanecarboxylicacetylamino)-cyclohexanecarboxylic phenyl)-acetonitrile acid[cyano-(3-hydroxy-phenyl)- acid methyl]-amide 77 cis-[2-((R)- and(S)-1-Cyano- A cis-2-Benzyloxycarbonylamino- 2-Amino- 385.51 386 (MH+)hexylcarbamoyl)-cyclohexyl]-carbamic cyclohexane carboxylic acidheptanenitrile; acid benzyl ester hydrochloride 78cis-2-(2-Phenoxy-acetylamino- B cis-2-Amino-cyclohexanecarboxylicPhenoxyacetyl 391.47 392 (MH+) cyclohexanecarboxylic acid ((R)- and acid(cyano-phenyl-methyl)-amide; chloride (S)-cyano-phenyl-methyl-amidecompound with trifluoro-acetic acid 79 trans-Isoxazole-5-carboxylic acid(2- C trans-2-[(Isoxazole-5-carbonyl)- Amino-(3-hydroxy- 368.39 368(MH+) {[cyano-(3-hydroxy-phenyl)-methyl]- amino]-cyclohexanecarboxylicacid phenyl)-acetonitrile carbamoyl}-cyclohexyl)-amide 80cis-2-(3-Cyclohexylcarbonylamino)- B cis-2-Amino-cyclohexanecarboxylicCyclohexane- 427.54 428 (MH+) cyclohexanecarboxylic acid [(R)- and acid[cyano-(3,4-dimethoxy-phenyl)- carboylicacid(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound with chloridemethyl]-amide trifluoro-acetic acid 81 (2-{[Cyano-(3-hydroxy-phenyl)- D2-(4-Trifluoromethyl- 2-Amino-2-(3- 475.47 476 (MH+)methyl]-carbamoyl}-cyclohexyl)- benzyloxycarbonylamino)- hydroxyphenyl)carbamic acid 4-trifluoromethyl-benzyl cyclohexanecarboxylic acidacetonitrile ester 82 cis-2-(Cyclobutanecarbonyl-amino)- Bcis-2-Amino-cyclohexanecarboxylic Cyclobutanecarbonyl 399.49 400 (MH+)cyclohexanecarboxylic acid [(R)- and acid [cyano-(3,4-dimethoxy-phenyl)-chloride (S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 83 cis-2-[2-(4-Chloro-phenyl- Bcis-2-Amino-cyclohexanecarboxylic 4-Chlorophenylacetyl 409.92 410 (MH+)acetylamino]-cyclohexanecarboxylic acid (cyano-phenyl-methyl)-amide;chloride acid ((R)- and (S)-cyano-phenyl- compound with trifluoro-aceticacid methyl-amide 84 cis-2-(Cyclopentanecarbonyl-amino- Bcis-2-Amino-cyclohexanecarboxylic Cyclopentanecarbonyl 353.46 354 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;chloride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 85 cis-2-[2-(4-Chloro-phenyl)- B cis-2-Amino-cyclohexanecarboxylic4-Chlorophenylacetic 469.97 470 (MH+) acetylamino]-cyclohexanecarboxylicacid [cyano-(3,4-dimethoxy-phenyl)- acid chloride acid [(R)- and(S)-cyano-(3,4- methyl]-amide; compound withdimethoxy-phenyl)-methyl]-amide trifluoro-acetic acid 86 (1S,2R)-{2-(R)-and (S)-[(Cyano- A-2 (1S,2R)-2-Benzyloxycarbonylamino- Amino-phenyl-391.47 390 (M − H) phenyl-methyl)-carbamoyl]- cyclohexane carboxylicacid acetonitrile; cyclohexyl}-carbamic acid benzyl ester hydrochloride87 (1S,2R)-(2-(R)- and (S)-{[Cyano-(3- A-2(1S,2R)-2-Benzyloxycarbonylamino- Amino-(3-methoxy- 421.5 439 (MNH4+)methoxy-phenyl)-methyl]-carbamoyl}- cyclohexane carboxylic acidphenyl)-acetonitrile; cyclohexyl)-carbamic acid benzyl esterhydrochloride 88 trans-N-(2-{[Cyano-(3-hydroxy- Ctrans-2-[(Quinoxaline-2-carbonyl)- Amino-(3-hydroxy- 429.48 430 (MH+)phenyl)-methyl]-carbamoyl}- amino]-cyclohexanecarboxylic acidphenyl)-acetonitrile cyclohexyl)-4-fluoro-benzamide 89cis-2-(2-Benzyloxy-acetylamino)- B cis-2-Amino-cyclohexanecarboxylicBenzyloxyacetyl 465.55 466 (MH+) cyclohexanecarboxylic acid [(R)- andacid [cyano-(3,4-dimethoxy-phenyl)- chloride(S)-cyano-(3,4-dimethoxy-phenyl)- methyl]-amide; compound withmethyl]-amide trifluoro-acetic acid 90 trans-2-(2-Thiophen-2-yl- Ctrans-2-(2-Thiophen-2-yl- Amino-(3-hydroxy- 397.5 398 (MH+)acetylamino)-cyclohexanecarboxylic acetylamino)-cyclohexanecarboxylicphenyl)-acetonitrile acid [cyano-(3-hydroxy-phenyl)- acid methyl]-amide91 cis-[2-((R)- and (S)-1-Cyano- A cis-2-Benzyloxycarbonylamino-2-Amino- 343.42 344( MH+) propylcarbamoyl)-cyclohexyl]-carbamiccyclohexane carboxylic acid butyronitrile; acid benzyl esterhydrochloride 92 cis-2-Phenylacetylamino- Bcis-2-Amino-cyclohexanecarboxylic Phenylacetyl chloride 375.47 376 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;398 (MNa+) (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 93 cis-2-(2-Benzyloxy-acetylamino- Bcis-2-Amino-cyclohexanecarboxylic Benzyloxyacetyl 405.5 406 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;chloride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 94 cis-2-(Cyclopropanecarbonyl-amino- Bcis-2-Amino-cyclohexanecarboxylic Cyclopropanecarbonyl 325.41 326 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;chloride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 95 cis-2-(3-Cyclopentyl-propionylamino- Bcis-2-Amino-cyclohexanecarboxylic Cyclopentyl-propionyl 381.52 382 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;chloride (S)-cyano-phenyl-methyl-amide compound with trifluoro-aceticacid 96 cis-2-(Cyclopentanecarbonyl-amino)- Bcis-2-Amino-cyclohexanecarboxylic Cyclopentanecarbonyl 413.52 414 (MH+)cyclohexanecarboxylic acid [(R)- and acid (cyano-phenyl-methyl)-amide;chloride (S)-cyano-(3,4-dimethoxy-phenyl)- compound withtrifluoro-acetic acid methyl]-amide 97 trans-Thiophene-2-carboxylic acid(2- C trans-2-[(Thiophene-2-carbonyl)- Amino-(3-hydroxy- 383.47 384(MH+) {[cyano-(3-hydroxy-phenyl)-methyl]- amino]-cyclohexanecarboxylicacid phenyl)-acetonitrile carbamoyl}-cyclohexyl)-amide 98cis-2-(3-Phenyl-propionylamino- B cis-2-Amino-cyclohexanecarboxylic3-Phenylpropionyl 389.5 390 (MH+) cyclohexanecarboxylic acid ((R)- andacid (cyano-phenyl-methyl)-amide; chloride (S)-cyano-phenyl-methyl-amidecompound with trifluoro-acetic acid 99 cis-2-Phenylmethanesulfonylamino-B cis-2-Amino-cyclohexanecarboxylic alpha- 411.52 412 (MH+)cyclohexanecarboxylic acid ((R)- and acid (cyano-phenyl-methyl)-amide;Toluenesulphonyl 434 (MNa+) (S)-cyano-phenyl-methyl-amide compound withtrifluoro-acetic acid chloride 100 trans-(2-{[Cyano-(3-methoxy-phenyl)-A-2 trans-2-Benzyloxycarbonylamino- Amino-(3-methoxy- 421.5 439 (MNH4+)methyl]-carbamoyl}-cyclohexyl)- cyclohexane carboxylic acidphenyl)-acetonitrile; carbamic acid benzyl ester hydrochloride 101cis-2-(4-Ethoxy-phenylamino)- E 2-(4-Ethoxyphenylamino)- 2-Amino-2-(3-393.49 394 (MH+) cyclohexanecarboxylic acid [cyano-(3- cyclohexanecarboxylic acid hydroxyphenyl) hydroxy-phenyl)-methyl]-amideacetonitrile 102 2-(4-Ethoxy-phenylamino)- E 2-(4-Ethoxyphenylamino)-Amino-phenyl- 377.49 378 (MH+) cyclohexanecarboxylic acid (cyano-cyclohexane carboxylic acid acetonitrile; phenyl-methyl)-amidehydrochloride 103 cis-2-(4-Ethoxy-phenylamino)- E2-(4-Ethoxyphenylamino)- Amino-(3-bromo- 456.39 456 (MH+)cyclohexanecarboxylic acid [(3-bromo- cyclohexane carboxylic acidphenyl)-acetonitrile phenyl)-cyano-methyl]-amide hydrochloride 104cis-2-(4-Ethoxy-phenylamino)- E 2-(4-Ethoxyphenylamino)- Amino- 421.5422 (MH+) cyclohexanecarboxylic acid cyclohexane carboxylic acidbenzo[1,3]dioxol-5- (benzo[1,3]dioxol-5-yl-cyano-methyl)-yl-acetonitrile; amide hydrochloride 105 cis-2-(4-Ethoxy-phenylamino)- E2-(4-Ethoxyphenylamino)- Amino-(4-methoxy- 407.52 408 (MH+)cyclohexanecarboxylic acid [cyano-(4- cyclohexane carboxylic acidphenyl)-acetonitrile; methoxy-phenyl)-methyl]-amide hydrochloride 106cis-2-Phenylamino- E cis-2-Phenylamino-cyclohexane Amino- 377.45 378(MH+) cyclohexanecarboxylic acid carboxylic acid benzo[1,3]dioxol-5-(benzo[1,3]dioxol-5-yl-cyano-methyl)- yl-acetonitrile; amidehydrochloride 107 2-Phenylamino-cyclohexanecarboxylic Ecis-2-Phenylamino-cyclohexane Amino-phenyl- 333.44 334 (MH+) acid(cyano-phenyl-methyl)-amide carboxylic acid acetonitrile; hydrochloride108 cis-(2-{(R)- and (S)-[Cyano-(3,4- A cis-2-Benzyloxycarbonylamino-Amino-(3,4- 437.49 438 (MH+) dimethoxy-phenyl)-methyl]- cyclopentanecarboxylic acid dimethoxy-phenyl)- carbamoyl}-cyclopentyl)-carbamic acidacetonitrile; benzyl ester hydrochloride 109trans-(2-{[3-Chloro-phenyl-cyano- A trans-2-Benzyloxycarbonylamino-Amino-(3-chloro- 411.89 412 (MH+) methyl]-carbamoyl}-cyclopentyl-cyclopentane carboxylic acid phenyl)-acetonitrile carbamic acid benzylester hydrochloride 110 trans-(2-{[Cyano-(3-methoxy-phenyl- Atrans-2-Benzyloxycarbonylamino- Amino-(3-methoxy- 407.47 425 (MNH+)methyl]-carbamoyl}-cyclopentyl- cyclopentane carboxylic acidphenyl)-acetonitrile; carbamic acid benzyl ester hydrochloride 111trans-{2-[(Cyano-phenyl-methyl- A trans-2-Benzyloxycarbonylamino-Amino-phenyl- 377.44 395 (MNH+) carbamoyl]-cyclopentyl}-carbamic acidcyclopentane carboxylic acid acetonitrile; benzyl ester hydrochloride112 trans-{2-[(Cyano-m-tolyl-methyl- A trans-2-Benzyloxycarbonylamino-Amino-m-tolyl- 391.47 492 (MH+) carbamoyl]-cyclopentyl}-carbamic acidcyclopentane carboxylic acid acetonitrile; benzyl ester hydrochloride113 Cis{2-[(Cyano-cyclopropyl-methyl)- A Cis-2-Benzyloxycarbonylamino-Amino-cyclopropyl- 355.44 356 (M + H) carbamoyl]-cyclohexyl}-carbamicacid cyclohexanecarboxylic acid acetonitrile benzyl ester 114Cis-[2-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid 2-349.82 351 (M + H) cyclohexyl]-carbamic acid 2-chloro-ylmethoxycarbonylamino)- chloro-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 115Cis-[2-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid 2-394.27 395 (M + H) cyclohexyl]-carbamic acid 2-bromo-ylmethoxycarbonylamino)- bromo-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 116Cis-[2-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid3-nitro- 360.37 361 (M + H) cyclohexyl]-carbamic acid 3-nitro-ylmethoxycarbonylamino)- benzyl ester 2,5-dioxo- benzyl estercyclohexanecarboxylic acid pyrrolidin-1-yl ester 117Cis-[4-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid 4-349.82 351 (M + H) cyclohexyl]-carbamic acid 4-chloro-ylmethoxycarbonylamino)- chloro-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 118Cis-[4-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid3,4- 384.27 385 (M + H) cyclohexyl]-carbamic acid 3,4-dichloro-ylmethoxycarbonylamino)- dichloro-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 119Cis-[4-(Cyanomethyl-carbamoyl)- G Cis-2-(9H-Fluoren-9- Carbonic acid 3-349.82 351 (M + H) cyclohexyl]-carbamic acid 3-chloro-ylmethoxycarbonylamino)- chloro-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 120Trans-[4-(Cyanomethyl-carbamoyl)- G Trans-2-(9H-Fluoren-9- Carbonic acid2- 349.82 351 (M + H) cyclohexyl]-carbamic acid 2-chloro-ylmethoxycarbonylamino)- chloro-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 121Trans-[4-(Cyanomethyl-carbamoyl)- G Trans-2-(9H-Fluoren-9- Carbonic acid2- 394.27 395 (M + H) cyclohexyl]-carbamic acid 2-bromo-ylmethoxycarbonylamino)- bromo-benzyl ester benzyl estercyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester 122Trans-[4-(Cyanomethyl-carbamoyl)- G Trans-2-(9H-Fluoren-9- Carbonic acid3-nitro- 360.37 361 (M + H) cyclohexyl]-carbamic acid 3-nitro-ylmethoxycarbonylamino)- benzyl ester 2,5-dioxo- benzyl estercyclohexanecarboxylic acid pyrrolidin-1-yl ester 123Trans-[4-(Cyanomethyl-carbamoyl)- G Trans-2-(9H-Fluoren-9- Carbonic acidphenyl 301.35 302 (M + H) cyclohexyl]-carbamic acid phenyl esterylmethoxycarbonylamino)- ester 2,5-dioxo- cyclohexanecarboxylic acidpyrrolidin-1-yl ester 124 Trans-[4-(Cyanomethyl-carbamoyl)- GTrans-2-(9H-Fluoren-9- Carbonic acid 3,4- 384.27 385 (M + H)cyclohexyl]-carbamic acid 3,4-dichloro- ylmethoxycarbonylamino)-dichloro-benzyl ester benzyl ester cyclohexanecarboxylic acid2,5-dioxo-pyrrolidin- 1-yl ester 125 Cis-5-Methoxy-benzofuran-2- HCis-2-(9H-Fluoren-9- 5-Methoxy- 355.4 356 (M + H) carboxylic acid[2-(cyanomethyl- ylmethoxycarbonylamino)- benzofuran-2-carbamoyl)-cyclohexyl]-amide cyclohexanecarboxylic acid carboxylic acid126 Trans-5-Methoxy-benzofuran-2- H Trans-2-(9H-Fluoren-9- 5-Methoxy-355.4 356 (M + H) carboxylic acid [2-(cyanomethyl-ylmethoxycarbonylamino)- benzofuran-2- carbamoyl)-cyclohexyl]-amidecyclohexanecarboxylic acid carboxylic acid 127Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-2-chloro-4-fluoro- 337.78 339 (M + H) cyclohexyl]-2-chloro-4-fluoro-ylmethoxycarbonylamino)- benzoic acid benzamide cyclohexanecarboxylicacid 128 Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-2-Methoxy-3-methyl- 329.4 330 (M + H) cyclohexyl]-2-methoxy-3-methyl-ylmethoxycarbonylamino)- benzoic acid benzamide cyclohexanecarboxylicacid 129 Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-2,6-dichloro-4- 368.27 369 (M + H) cyclohexyl]-2,6-dichloro-4-methoxy-ylmethoxycarbonylamino)- methoxy-benzoic acid benzamidecyclohexanecarboxylic acid 130 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 3-fluoro-4-methyl- 317.37 318 (M + H)cyclohexyl]-3-fluoro-4-methyl- ylmethoxycarbonylamino)- benzoic acidbenzamide cyclohexanecarboxylic acid 131Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9-3-chloro-4-methyl- 333.82 335 (M + H) cyclohexyl]-3-chloro-4-methyl-ylmethoxycarbonylamino)- benzoic acid benzamide cyclohexanecarboxylicacid 132 Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-3-bromo-4-methyl- 378.27 379 (M + H) cyclohexyl]-3-bromo-4-methyl-ylmethoxycarbonylamino)- benzoic acid benzamide cyclohexanecarboxylicacid 133 Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-4-cyanomethyl- 324.39 325 (M + H) cyclohexyl]-4-cyanomethyl-benzamideylmethoxycarbonylamino)- benzoic acid cyclohexanecarboxylic acid 134Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9- 3,5-di- 421.35422 (M + H) cyclohexyl]-3,5-di-trifluoromethyl- ylmethoxycarbonylamino)-trifluoromethyl- benzamide cyclohexanecarboxylic acid benzoic acid 135Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9-4-tert-butyl-benzoic 341.46 342 (M + H)cyclohexyl]-4-tert-butyl-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 136 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 3-chloro-6-methoxy- 349.82 351 (M + H)cyclohexyl]-3-chloro-6-methoxy- ylmethoxycarbonylamino)- benzoic acidbenzamide cyclohexanecarboxylic acid 137Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-3-chloro-6-methoxy- 349.82 351 (M + H) cyclohexyl]-3-chloro-6-methoxy-ylmethoxycarbonylamino)- benzoic acid benzamide cyclohexanecarboxylicacid 138 Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9-3-chloro-benzoic acid 319.79 321 (M + H) cyclohexyl]-3-chloro-benzamideylmethoxycarbonylamino)- cyclohexanecarboxylic acid 139Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9- 3-Acetylamino-342.4 343 (M + H) cyclohexyl]-3-acetylamino-benzamideylmethoxycarbonylamino)- benzoic acid cyclohexanecarboxylic acid 140Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-3-Acetylamino- 342.4 343 (M + H) cyclohexyl]-3-acetylamino-benzamideylmethoxycarbonylamino)- benzoic acid cyclohexanecarboxylic acid 141Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9- 4-Acetylamino-342.4 343 (M + H) cyclohexyl]-4-acetylamino-benzamideylmethoxycarbonylamino)- benzoic acid cyclohexanecarboxylic acid 142Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-4-Acetylamino- 342.4 343 (M + H) cyclohexyl]-4-acetylamino-benzamideylmethoxycarbonylamino)- benzoic acid cyclohexanecarboxylic acid 143Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9-4-Acetyl-benzoic acid 327.39 328 (M + H) cyclohexyl]-4-acetyl-benzamideylmethoxycarbonylamino)- cyclohexanecarboxylic acid 144Trans-N-[2-(Cyanomethyl-carbamoyl)- H Trans-2-(9H-Fluoren-9-4-Acetyl-benzoic acid 327.39 328 (M + H) cyclohexyl]-4-acetyl-benzamideylmethoxycarbonylamino)- cyclohexanecarboxylic acid 145Cis-N-[2-(Cyanomethyl-carbamoyl)- H Cis-2-(9H-Fluoren-9- 2-chloro-5-365.88 367 (M + H) cyclohexyl]-2-chloro-5-(methylthio)-ylmethoxycarbonylamino)- (methylthio)-benzoic benzamidecyclohexanecarboxylic acid acid 146 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 2,3-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-2,3-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 147 Trans-N-[2-(Cyanomethyl-carbamoyl)- HTrans-2-(9H-Fluoren-9- 2,3-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-2,3-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 148 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 2,4-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-2,4-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 149 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 2,5-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-2,5-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 150 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 2,6-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-2,6-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 151 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 3,4-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-3,4-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 152 Trans-N-[2-(Cyanomethyl-carbamoyl)- HTrans-2-(9H-Fluoren-9- 3,4-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-3,4-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 153 Cis-N-[2-(Cyanomethyl-carbamoyl)- HCis-2-(9H-Fluoren-9- 3,5-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-3,4-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 154 Trans-N-[2-(Cyanomethyl-carbamoyl)- HTrans-2-(9H-Fluoren-9- 3,5-dichloro-benzoic 354.24 355 (M + H)cyclohexyl]-3,5-dichloro-benzamide ylmethoxycarbonylamino)- acidcyclohexanecarboxylic acid 155 Cis-2-{[(4-chlorophenyl)acetyl]amino}- ICis-2-Amino-cyclohexanecarboxylic 4-Chlorophenyl-acetic 373.89 375 (M +H) N-[cyano(cyclopropyl)methyl]cyclo-acid(1-cyano-1-cyclopropyl-methyl)- acid hexanecarboxamide amide aceticacid salt 156 Cis-N-[cyano(cyclopropyl)methyl]-2- ICis-2-Amino-cyclohexanecarboxylic 3-(3-Methoxyphenyl)- 383.49 384 (M +H) {[3-(3- acid(1-cyano-1-cyclopropyl-methyl)- propionic acidmethoxyphenyl)propanoyl]amino}cyclo- amide acetic acid salthexanecarboxamide 157 Cis-N-[2- I Cis-2-Amino-cyclohexanecarboxylic4-Ethylbenzoic acid 353.47 354 (M + H)({[cyano(cyclopropyl)methyl]amino} acid(1-cyano-1-cyclopropyl-methyl)-carbonyl)cyclohexyl]-4-ethylbenzamide amide acetic acid salt 158Cis-N-[2- I Cis-2-Amino-cyclohexanecarboxylic 4-Ethoxybenzoic acid369.47 370 (M + H) ({[cyano(cyclopropyl)methyl]amino}acid(1-cyano-1-cyclopropyl-methyl)-carbonyl)cyclohexyl]-4-ethoxybenzamide amide acetic acid salt 159Cis-N-[2- F Cis-2-Amino-cyclohexanecarboxylic 4-Methoxybenzoyl 355.44356 (M + H) ({[cyano(cyclopropyl)methyl]amino}acid(1-cyano-1-cyclopropyl-methyl)- chloride carbonyl)cyclohexyl]-4-amide acetic acid salt methoxybenzamide 160 Trans-N-[2- F Trans-2-Amino-4-Methoxybenzoyl 355.44 356 (M + H) ({[cyano(cyclopropyl)methyl]amino}cyclohexanecarboxylic acid(1-cyano- chloride carbonyl)cyclohexyl]-4-1-cyclopropyl-methyl)-amide acetic methoxybenzamide acid salt 161Trans-N-[2- F Trans-2-Amino- 4-Ethylbenzoyl 353.47 354 (M + H)({[cyano(cyclopropyl)methyl]amino} cyclohexanecarboxylic acid(1-cyano-chloride carbonyl)cyclohexyl]-4-ethylbenzamide1-cyclopropyl-methyl)-amide acetic acid salt 162 Cis-N-[2- FCis-2-Amino-cyclohexanecarboxylic 3,4-Difluorobenzoyl 361.39 362 (M + H)({[cyano(cyclopropyl)methyl]amino} acid(1-cyano-1-cyclopropyl-methyl)-chloride carbonyl)cyclohexyl]-3,4- amide acetic acid saltdifluorobenzamide 163 Cis-N-[2- F Cis-2-Amino-cyclohexanecarboxylic4-Cyanobezoyl 350.42 351 (M + H) ({[cyano(cyclopropyl)methyl]amino}acid(1-cyano-1-cyclopropyl-methyl)- chloridecarbonyl)cyclohexyl]-4-cyanobenzamide amide acetic acid salt 164Cis-N-[2- F Cis-2-Amino-cyclohexanecarboxylic 4-tert-Butylbenzoyl 381.52383 (M + H) ({[cyano(cyclopropyl)methyl]amino}acid(1-cyano-1-cyclopropyl-methyl)- chloridecarbonyl)cyclohexyl]-4-tert- amide acetic acid salt butylbenzamide 165Cis-N-[2- F Cis-2-Amino-cyclohexanecarboxylic 3,4,5-Trimethoxy 415.49416 (M + H) ({[cyano(cyclopropyl)methyl]amino}acid(1-cyano-1-cyclopropyl-methyl)- benzoyl chloridecarbonyl)cyclohexyl]-3,4,5- amide acetic acid salt trimethoxybenzamide

[0377] The following methods were used:

[0378] METHOD A: Coupling of protected amino acids with amino nitriles

[0379] A solution of 1 eq cis-2-Benzyloxycarbonylamino-cyclohexanecarboxylic acid, 7 eq N-methylmorpholin, 0.2 eq HOBT and 2.4 eq EDCI in7 ml CH₂Cl₂ is added to 1.1-1.3 eq amino nitrile-HCl. After shakingovernight the reaction mixture is extracted with 1N HCl and the CH₂Cl₂is evaporated. The compounds are purified by HPLC:

[0380] column: HP-CombiHT XDB-C18, 21.2 mmI.D.×50 mm, Series No DN 1020

[0381] method: Flow: 40 ml/min

[0382] 0 min 80% water, 20% acetonitrile

[0383] 0.2 min 80% water, 20% acetonitrile

[0384] 3.5 min 5% water, 95% acetonitrile

[0385] 4.7 min 5% water, 95% acetonitrile

[0386] 4.8 min 80% water, 20% acetonitrile

[0387] 4.9 min 80% water, 20% acetonitrile

[0388] machine: Prep HPLC System Dynamax Model SD-1, UV-1

[0389] METHOD A-2:

[0390] The protected amino acid, the amino nitrile, TPTU(O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate) and Htinigsbase (N-Ethyldiisopropylamine) aredissolved in MeCN. The mixture is stirred at RT for 6-16 h. The solutionis concentrated and the residue is dissolved in ethyl acetate andextracted with H₂O. The H₂O layers are extracted with ethyl acetate. Thecombined ethyl acetate layers are washed with NaHCO₃, brine, dried overNa₂SO₄ and evaporated. The crude product is purified by columnchromatography.

[0391] Yield 60-90%

[0392] METHOD B:

[0393] Crude mixture of amino acid-amide-trifluoroacetate (educt 1)+a.Carbonylchloride (educt 2) or b. sulfonylchloride (educt2)+triethylamine To a solution of 1 eq 2-Amino-cyclohexanecarboxylicacid amide; compound with trifluoro-acetic acid (educt 1) in CH₂Cl₂ isadded a solution of 1.1 eq carbonylchloride (educt 2) orsulfonylchloride (educt 2) or isothiocyanate (educt 2) in CH₂Cl₂. Tothis mixture is added 2.1 eq triethylamine. After shaking overnight atRT formic acid is added, CH₂Cl₂ is evaporated and the compound purifiedby HPLC:

[0394] column: HP-CombiHT XDB-C18, 21.2 mmI.D.×50 mm, Series No DN 1020

[0395] method: Flow: 40 ml/min

[0396] 0 min 80% water, 20% acetonitrile

[0397] 0.2 min 80% water, 20% acetonitrile

[0398] 3.5 min 5% water, 95% acetonitrile

[0399] 4.7 min 5% water, 95% acetonitrile

[0400] 4.8 min 80% water, 20% acetonitrile

[0401] 4.9 min 80% water, 20% acetonitrile

[0402] machine: Prep HPLC System Dynamax Model SD-1, UV-1

[0403] METHOD C:

[0404] The trans-cyclohexane carboxylic acid (eductl, 1 equiv) isdissolved in dry CH₃CN (0.2 M). A solution of TPTU (1 equiv), DIPEA (4equiv) in dry CH₃CN (0.2 M) is added to the solution at rt. Theamino-(3-hydroxy-phenyl)-acetonitrile (educt 2,1 equiv) dissolved inCH₃CN (0.2 M) is added and the mixture is stirred overnight. Thereaction mixture is filtered and concentrated. The residue is dissolvedin lmL of CH₃CN and purified by HPLC.

[0405] column: YMC; CombiPrep ODS_AQ; 50*20 mml.D; S-5 um, 120A

[0406] method: Flow: 40 ml/min

[0407] 0 min 90% water, 10% acetonitrile

[0408] 0.1 L 90% water, 10% acetonitrile

[0409] 3.5 min 5% water, 95% acetonitrile

[0410] 5.5 min 5% water, 95% acetonitrile

[0411] 5.7 min 80% water, 20% acetonitrile

[0412] 5.8 min 80% water, 20% acetonitrile

[0413] machine: Prep HPLC System Dynamax Model SD-1, UV-1.

[0414] METHOD D:

[0415] The reaction can be conveniently carried out by dissolving thetrans-amino carbonyloxy-cyclohexane carboxylic acid (educt 1) in DMF andadding TPTU (1 equiv), Hunigsbase (4 equiv), the2-Amino-2-(3-hydroxy-phenyl)-acetonitrile (educt 2, 1 equiv) in DMF andstirring the mixture at room temperature for 16 hours. The reactionmixture can be filtered and the product can be obtained by HPLC.

[0416] column: YMC; CombiPrep ODS_AQ; 50*20 mml.D; S-5 um, 120A

[0417] method: Flow: 40 ml/min

[0418] 0 min 90% water, 10% acetonitrile

[0419] 0.1 L 90% water, 10% acetonitrile

[0420] 3.5 min 5% water, 95% acetonitrile

[0421] 5.5 min 5% water, 95% acetonitrile

[0422] 5.7 min 80% water, 20% acetonitrile

[0423] 5.8 min 80% water, 20% acetonitrile

[0424] machine: Prep HPLC System Dynamax Model SD-1, UV-1.

[0425] Conveniently, the trans-amino carbonyloxy-cyclohexane carboxylicacid (educt 1) is obtained by adding the mixed carbonate in THF(prepared from the corresponding alcohol, 4-Nitrophenylchloroformate andpyridine in CH₂Cl₂) to the corresponding amino acid dissolved in aqueous10% NaHCO₃. The reaction mixture is vigorously stirred at roomtemperature for 16 hours. After completion of the reaction, theresulting compound is isolated by methods known to the person skilled inthe art, e.g. by extraction.

[0426] METHOD E:

[0427] A solution of 2-Phenylamino-cyclohexane carboxylic acid (educt 1,1 eq), 3eq N-ethyldiisopropylamine and 1 eq TPTU in acetonitrile isadded to 1 eq Amino-phenyl-acetonitrile hydrochloride (educt 2). Afterstirring overnight the solvent is evaporated. The residue is dissolvedin ethyl acetate, washed with sodium hydrogencarbonate solution (3×) andbrine. The solution is dried over sodium sulfate and evaporated. Thecompound is purified by flash chromatography (silicagel).

[0428] METHOD F:

[0429] DIPEA (diisopropylethylamine) (3 equivalents) is added to asolution of 2-Amino-cyclohexanecarboxylicacid(1-cyano-1-cyclopropyl-methyl)-amide acetic acid salt (1 equivalent)in CH₂Cl₂ (anhydrous, 5 ml) and the mixture is stirred at roomtemperature for 45 minutes. The acid chloride (1 equivalent) is addedand the reaction mixture is stirred at room temperature under N₂overnight. The reaction mixture is diluted with CH₂Cl₂, washed with 1Naqueous HCl and saturated NaHCO₃, dried over MgSO₄, filtered andconcentrated. The residue is purified by preparative TLC (silica;hexane: EtOAc 1:1) to give the product as a white solid. Yield: 60-85%.

[0430] METHOD G:

[0431] To 1 eq of Rink resin bound glycine in DMF is added 3 eq. ofEduct 1, 3 eq. EDCI, 1 eq. HOBT, and 9 eq. NMM. The reaction is shakenovernight at RT. The solvent is removed and the resin washed three timeswith dichloromethane, 3 times with methanol, and again three times withdichloromethane. The resin is then suspended in DMF and 20% piperidineis added. After 30 minutes reaction time at RT, the solvent is removedby filtration. The resin is washed three times with dichloromethane, 3times with methanol, and again three times with dichloromethane. Theresin is again suspended in DMF and 3 eq. of the succinimidyl carbonate(educt 2) is added. The reaction is shaken overnight at RT. The resin isthen filtered and washed three times with dichloromethane, 3 times withmethanol, and again three times with dichloromethane. The resin is thensuspended in a 10% solution of trifluoroacetic acid in dichloromethane.After 30 minutes reaction time at room temperature, the resin isfiltered and washed once with dichloromethane. The filtrate isconcentrated to dryness to yield the amide. The amide is subjected todehydration using Burgess reagent. The amide is diluted indichloromethane or in the trans case 1,4-dioxane. One eq. of Burgess isadded and the reaction stirred for 2 h at RT, afterwhich a second eq. ofBurgess is added and the reaction stirred for an additional 2 h. Thecrude reaction mixture is evaporated to dryness and then diluted inethyl acetate. The organic layer is washed with 10% bicarbanatesolution, water, and brine. The organic layer is then dryed, filteredand evaporated to dryness. When purification is necessary, it is carriedout using HPLC.

[0432] Shimadzu HPLC Pump Initial Conditions

[0433] A% 80, (H2O (0.1 TFA))

[0434] B% 20, (CH3CN)

[0435] Flow (mL/min): 2.500

[0436] Stop time (mins): 10.0

[0437] High pressure (psi): 4000

[0438] Low Pressure (psi): 0

[0439] Set Temp (C): 40

[0440] Temperature Limit (C): 45

[0441] Shimadzu HPLC Pump Gradient Timetable

[0442] The gradient timetable contains 5 entries which are:

[0443] Time, A%, B%, Flow, Curve

[0444] 1.00, 80, 20, 2.50, 6

[0445] 3.00, 65, 35, 2.50, 6

[0446] 5.00, 45, 55, 2.50, 6

[0447] 7.00, 75, 25, 2.50, 6

[0448] 10.00, 80, 20, 2.50, 6

[0449] METHOD H:

[0450] To 1 eq of Rink resin bound glycine in DMF is added 3 eq. ofEduct 1, 3 eq. EDCI, 1 eq. HOBT, and 9 eq. NMM. The reaction is shakenovernight at RT. The solvent is removed and the resin washed three timeswith dichloromethane, 3 times with methanol, and again three times withdichloromethane. The resin is then suspended in DMF and 20% piperidineis added. After 30 minutes reaction time at RT, the solvent is removedby filtration. The resin is washed three times with dichloromethane, 3times with methanol, and again three times with dichloromethane. Theresin is again suspended in DMF and 3 eq. of the carboxylic acid (educt2) is added, along with 3 eq. EDCI, 1 eq. HOBT, and 9 eq. NMM. Thereaction is shaken overnight at RT. The resin is then filtered andwashed three times with dichloromethane, 3 times with methanol, andagain three times with dichloromethane. The resin is then suspended in a10% solution of trifluoroacetic acid in dichloromethane. After 30minutes reaction time at RT, the resin is filtered and washed once withdichloromethane. The filtrate is concentrated to dryness to yield theamide. The amide is subjected to dehydration using Burgess reagent. Theamide is diluted in dichloromethane or in the trans case 1,4-dioxane.One eq. of Burgess is added and the reaction stirred for 2 h at RT,afterwhich a second eq. Of Burgess is added and the reaction stirred foran additional 2 h. The crude reaction mixture is evaporated to drynessand then diluted in ethyl acetate. The organic layer is washed with 10%bicarbanate solution, water, and brine. The organic layer is then dryed,filtered and evaporated to dryness. When purification is necessary, itis carried out using HPLC.

[0451] Method I

[0452] HOBT (2 equivalents) is added to the solution of the acid (educt2,1 equivalent) in DMF (anhydrous, 5 ml) and the mixture is stirred atroom temperature for 1 hour. 2-amino-cyclohexanecarboxylicacid(1-cyano-1-cyclopropyl-methyl)-amide acetic acid salt (1 equivalent), EDCI (2 equivalents) and NMM (6 equivalents) are added and themixture is stirred at room temperature under N₂ overnight andconcentrated. The residue is dissolved in CH₂Cl₂, washed with diluteaqueous HCl and saturated NaHCO₃, dried over MgSO₄, filtered andconcentrated. The residue is purified by preparative TLC (silica;hexane:EtOAc 2:1) to give the product as a white solid. Yield: 65-85%.

EXAMPLE 9

[0453] Preparation of 2-Amino-2-cyclopropyl-acetonitrile hydrochloride

[0454] Sodium cyanide (3.5 g, 71.4 mmol) and ammomium chlorid (3.82 g,71.4 mmol) are dissolved in H₂O (20 ml) and MeOH (20 ml) and thesolution is cooled to 0° C. A solution of cyclopropanecarboxaldehyde(5.0 g, 71.3 mmol) in MeOH (15 ml) and CH₂Cl₂ (15 ml) is added dropwiseto the above cooled mixture over 20 minutes. The mixture is stirred at0° C. for 30 minutes and ammonium hydroxide (28% NH₃ in H₂O, 8.64 ml,142.8 mmol) is added. The reaction mixture is allowed to warm to roomtemperature overnight and concentrated. The residue is partitionedbetween H₂O and CH₂Cl₂. The organic layer is separated, dried overMgSO₄, filtered and concentrated to give a clear oil. This clear oil isdissolved in Et₂O (50 ml) and 4N HCl in dioxane is added slowly. Thewhite precipitate is filtered, washed with Et₂O, and dried in vacuo for2 hours to give the product as a white powder. Yield: 7.89 g, 83.9%.

[0455] Preparation of{2-[(1-cyano-1-cyclopropyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester

[0456] A solution of 2-Benzyloxycarbonyl-amino-cyclohexane carboxylicacid (1.46 g, 5.26 mmol), 2-Amino-2-cyclopropyl-acetonitrilehydrochloride (0.70 g, 5.27 mmol ), 1-hydroxybenzotriazole (0.89 g, 5.82mmol) and N-methylmorpholine (1.07 g, 10.58 mmol) in DMF is cooled to 0°C. and treated with 1-ethyl-3-(3-dimethylamino)propyl carbodiimidehydrochloride (2.02 g, 10.54 mmol). The reaction mixture is allowed towarm to room temperature overnight and concentrated. The residue isdissolved in CH₂Cl₂, washed with dilute aqueous HCl and saturatedaqueous NaHCO₃, dried over MgSO₄, filtered and concentrated to give abrown oil. This brown oil is purified via flash chromatograhy withhexane:EtOAc 6:1 to 3:1 to give the product as a white foam.

[0457] Yield: 1.55 g, 82.8%.

[0458] Preparation of 2-Amino-cyclohexanecarboxylic acid(1-cyano-1-cyclopropyl-methyl)-amide acetic acid salt

[0459] To a solution of2-[(1-cyano-1-cyclopropyl-methyl)-carbamoyl]-cyclohexyl-carbamic acidbenzyl ester (0.15 g, 0.42 mmol) in 50 ml EtOAc with 1% HOAc (v/v) isadded Pd/C (10%) (0.05 g) carefully under nitrogen. The mixture isdegassed completely before the reaction flask is filled with H₂ througha balloon. The reaction mixture is stirred for 45 minutes. TLC showedthat the starting material has disappeared. The reaction mixture isfiltered through Celite. The filtrate is concentrated to give a yellowoil. Yield: 0.17 g, 100%. The isolated cis- and trans-forms of theproduct are obtained by starting from the corresponding cis- ortrans-form of the cyclohexane derivative.

EXAMPLE 10

[0460] PreparationCis-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-cyclohexanecarboxylic acid

[0461] Cis Beta amino cyclohexane carboxylic acid (1 g, 7 mmol) isdissolved in 18 mL of a 10% solution of NaCO₃ in water. Dioxane (10.5mL) is added and the solution is cooled in an ice bath. FMOC chloride(1.8 g, 7 mmol.) is added in portions and stirring is continued for 4 hin the ice bath. The reaction mixture is allowed to warm to roomtemperature overnight. The reaction is quenched by the addition of waterto homogeneity. The aqueous layer is washed with ether twice and thenacidified. The acidic layer is extracted with dichloromethane 3×100 mL.The combined organic layers are dried with sodium sulfate and thereaction mixture is condensed in vacuo. The solid material is purifedusing flash chromatography 1:1:0.16 hexanes:ethyl acetate:acetic acid. A50% yield of pure material is obtained MS 366.2 (M+H).

[0462] PreparationTrans-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-cyclohexanecarboxylic acid

[0463] Trans beta amino cyclohexane carboxylic acid (1 g, 7 mmol) isdissolved in 18 mL of a 10% solution of NaCO₃ in water. Dioxane (10.5mL) is added and the solution is cooled in an ice bath. FMOC chloride(1.8 g, 7 mmol.) is added in portions and stirring is continued for 4 hin the ice bath. The reaction mixture is allowed to warm to roomtemperature overnight. The reaction is quenched by the addition of waterto homogeneity. The aqueous layer is washed with ether twice and thenacidified. Upon acidification the desired material precipitates. Theprecipitate is filtered and washed and the white product is used withoutpurification.

EXAMPLE A

[0464] Tablets containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per tablet Compound of formula I10.0-100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mgMagnesium stearate 1.0 mg

EXAMPLE B

[0465] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula I25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg

EXAMPLE C

[0466] Injection solutions can have the following composition: Compoundof formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water for injectionsolutions ad 1.0 ml

What is claimed is:
 1. A compound selected from the group consisting ofcompounds of formula (I)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2;pharmaceutically acceptable salts of compounds of formula (I); andpharmaceutically acceptable esters of compounds of formula (I).
 2. Thecompound of claim 1, wherein n is
 1. 3. The compound of claim 2, whereinR² is H.
 4. The compound of claim 3, wherein R³ is H.
 5. The compound ofclaim 4, wherein R⁴ is H.
 6. The compound of claim 5, wherein R¹ is—CO—R^(a).
 7. The compound of claim 6, wherein R^(a) is selected fromthe group consisting of benzyloxy, phenylvinylene,thiophen-2-yl-methylene-oxy and thiophen-3-yl-methylene-oxy.
 8. Thecompound of claim 7, wherein R^(a) is benzyloxy.
 9. The compound ofclaim 8, which is cis-(2-{(R)- and(S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclopentyl)-carbamicacid benzyl ester.
 10. The compound of claim 8, which istrans-(2-{[(3-chloro-phenyl-cyano-methyl]-carbamoyl}-cyclopentyl-carbamicacid benzyl ester.
 11. The compound of claim 8, which istrans-(2-{[cyano-(3-methoxy-phenyl-methyl]-carbamoyl}-cyclopentyl-carbamicacid benzyl ester.
 12. The compound of claim 8, which istrans-{2-[(cyano-phenyl-methyl-carbamoyl]-cyclopentyl}-carbamic acidbenzyl ester.
 13. The compound of claim 8, which istrans-{2-[(cyano-m-tolyl-methyl-carbamoyl]-cyclopentyl}-carbamic acidbenzyl ester.
 14. The compound of claim 5, wherein R⁵ is aryl.
 15. Thecompound of claim 14, wherein R⁵ is selected from the group consistingof benzo[1,3]dioxyl, phenyl and napthyl, wherein the phenyl or napthylis optionally substituted with lower-alkyl, halogen, hydroxy,lower-alkoxy or lower-alkyl-carbonyloxy.
 16. The compound of claim 15,wherein R⁵ is selected from the group consisting of phenyl,3-hydroxy-phenyl, 3-methoxy-phenyl, 4-methoxyl-phenyl, 3-methyl-phenyl,2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3-chloro-phenyl,3-bromo-phenyl, 4-bromo-phenyl and benzo [1,3]dioxol-5-yl.
 17. Thecompound of claim 5, wherein R⁵ is hydrogen.
 18. The compound of claim5, wherein R⁵ is cycloalkyl.
 19. The compound of claim 1, wherein n is2.
 20. The compound of claim 19, wherein R² is hydrogen.
 21. Thecompound of claim 20, wherein R³ is hydrogen.
 22. The compound of claim21, wherein R⁴ is hydrogen.
 23. The compound of claim 22, wherein R⁵ islower-alkyl.
 24. The compound of claim 23, wherein R¹ is —CO—R^(a). 25.The compound of claim 24, wherein R^(a) is selected from the groupconsisting of benzyloxy, phenylvinylene, thiophen-2-yl-methylene-oxy andthiophen-3-yl-methylene-oxy.
 26. The compound of claim 25, wherein R^(a)is benzyloxy.
 27. The compound of claim 26, which is cis-[2-((R)- and(S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-carbamic acid benzylester.
 28. The compound of claim 26, which is cis-[2-((R)- and(S)-1-cyano-hexylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester. 29.The compound of claim 26, which is cis-[2-((R)- and(S)-1-cyano-propylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester. 30.The compound of claim 22, wherein R⁵ is aryl.
 31. The compound of claim30, wherein R⁵ is phenyl or naphthyl, optionally substituted withlower-alkyl, halogen, hydroxy, lower-alkoxy or lower-alkyl-carbonyloxy,or wherein R⁵ represents benzo [1,3]dioxyl.
 32. The compound of claim31, wherein R⁵ represents phenyl or naphthyl, optionally substitutedwith hydroxy, methoxy, methyl, acetoxy, chlorine or bromine or whereinR⁵ represents benzo [1,3]dioxyl.
 33. The compound of claim 32, whereinR⁵ is napthyl optionally substituted with hydroxy, methoxy, methyl,acetoxy, chlorine or bromine.
 34. The compound of claim 33, wherein R⁵is napthyl.
 35. The compound of claim 34, which is cis-{2-[(R)- and(S)-(cyano-naphthalen-2-yl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 36. The compound of claim 34, which is cis-{2-[(R)- and(S)-(cyano-naphthalen-1-yl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 37. The compound of claim 32, wherein R⁵ is phenyloptionally substituted with hydroxy, methoxy, methyl, acetoxy, chlorineor bromine.
 38. The compound of claim 37, which is cis-(2-{(R)- and(S)-[(4-chloro-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 39. The compound of claim 37, which is cis-aceticacid 4-(R)- and(S)-[(2-benzyloxycarbonylamino-cyclohexanecarbonyl)-amino]-cyano-methyl}-phenylester.
 40. The compound of claim 37, which istrans-(2-{[(3-bromo-4-methoxy-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 41. The compound of claim 37, which istrans-(2-{[(3-bromo-4-methoxy-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 42. The compound of claim 37, which is cis-(2-{(R)-and(S)-[cyano-(2,4-dimethyl-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 43. The compound of claim 32, wherein R⁵ is selectedfrom the group consisting of phenyl, 3-hydroxy-phenyl, 3-methoxy-phenyl,4-methoxy-phenyl, 3-methyl-phenyl, 2,4-dimethoxy-phenyl,3,4-dimethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyland benzo [1,3]dioxol-5-yl.
 44. The compound of claim 43, wherein R⁵ isphenyl.
 45. The compound of claim 44, wherein R¹ is —CO—R^(a).
 46. Thecompound of claim 45, wherein R^(a) is cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyloxy, aryl, aryloxy, aryl-lower-alkyl,aryl-lower-alkoxy, aryloxy-lower-alkyl, aryl-S-lower-alkyl,aryl-lower-alkenyl, or heteroaryl-lower-alkoxy.
 47. The compound ofclaim 46, which iscis-2-(2-phenylsulfanyl-acetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 48. The compound of claim 46, which iscis-2-(3-cyclopentyl-propionylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 49. The compound of claim 46, whereinR^(a) is cycloalkyl.
 50. The compound of claim 49, which iscis-2-(cyclopentanecarbonyl-amino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 51. The compound of claim 49, which iscis-2-(cyclopropanecarbonyl-amino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 52. The compound of claim 46, whereinR^(a) is aryl-lower-alkyl.
 53. The compound of claim 52, which iscis-2-(3-phenyl-propionylamino)-cyclohexanecarboxylic acid(cyano-phenyl-methyl)-amide.
 54. The compound of claim 52, which iscis-2-(3-phenyl-propionylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 55. The compound of claim 46, whereinR^(a) is aryloxy-lower-alkyl.
 56. The compound of claim 55, which iscis-2-[2-(4-chloro-phenoxy-acetylamino]-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide.
 57. The compound of claim 55, whichis cis-2-(2-phenoxy-acetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 58. The compound of claim 55, which iscis-2-(2-benzyloxy-acetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 59. The compound of claim 46, whereinR^(a) is phenyl optionally substituted with at least one group selectedfrom phenyl, cyano, and fluoro; or R^(a) is benzyloxy optionallysubstituted with at least one group selected from methyl, chloro,fluoro, methoxy, nitro, and CF₃; or R^(a) is phenylvinylene,thiophenyl-methylene-oxy, cyclopentyloxy, thiophenyl-ethylene-oxy,naphthyloxy, thiophenyl-trimethylene-oxy, or phenoxy.
 60. The compoundof claim 59, which is cis-{2-[(R)- and(S)-(cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acidnaphthalen-2-yl ester.
 61. The compound of claim 59, which iscis-{2-[(R)- and(S)-(cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acid phenylester.
 62. The compound of claim 59, which is cis-{2-[(R)- and(S)-(cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acid4-nitro-benzyll ester.
 63. The compound of claim 59, which iscis-{2-[(R)- and(S)-(cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-carbamic acidcyclopentyl ester.
 64. The compound of claim 59, wherein R^(a) isbenzyloxy, phenylvinylene, thiophen-2-yl-methylene-oxy, orthiophen-3-yl-methylene-oxy.
 65. The compound of claim 64, which iscis-2-(3-phenyl-acryloylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 66. The compound of claim 64, whereinR^(a) is benzyloxy.
 67. The compound of claim 66, which is(R)-{2-[(S)-(cyano-phenyl-methyl)-(R)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester.
 68. The compound of claim 66, which issyn-{2-[(S)-(cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 69. The compound of claim 66, which iscis-{2-[(cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 70. The compound of claim 66 which istrans-{2-[(cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 71. The compound of claim 66, which is (1S,2R)-{2-(R)- and(S)-[(cyano-phenyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester.
 72. The compound of claim 46, wherein R^(a) is benzyl optionallysubstituted with chloro, or phenyl optionally substituted withlower-alkyl, lower-alkoxy, or cyano.
 73. The compound of claim 72, whichis cis-N-{2-[(R)- and(S)-(cyano-phenyl-methyl-carbamoyl]-cyclohexyl}-benzamide.
 74. Thecompound of claim 72, which iscis-2-[2-(4-chloro-phenyl-acetylamino]-cyclohexanecarboxylic acid ((R)-and (S)-cyano-phenyl-methyl-amide.
 75. The compound of claim 72, whichis cis-2-phenylacetylamino-cyclohexanecarboxylic acid ((R)- and(S)-cyano-phenyl-methyl-amide.
 76. The compound of claim 72, whereinR^(a) is 4-ethyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl,4-cyano-phenyl, 4-tert.-butyl-phenyl, or 4-chloro-benzyl.
 77. Thecompound of claim 46, wherein R^(a) is heteroaryl.
 78. The compound ofclaim 46, wherein R^(a) is 5-methoxy-benzofuran-2-yl.
 79. The compoundof claim 44, wherein R¹ is —SO₂—R^(b).
 80. The compound of claim 79,which is cis-2-phenylmethanesulfonylamino-cyclohexanecarboxylic acid((R)- and (S)-cyano-phenyl-methyl-amide.
 81. The compound of claim 44,wherein R¹ is phenyl, optionally substituted with ethoxy.
 82. Thecompound of claim 81, which is2-(4-ethoxy-phenylamino)-cyclohexanecarboxylic acid(cyano-phenyl-methyl)-amide.
 83. The compound of claim 81, which is2-phenylamino-cyclohexanecarboxylic acid (cyano-phenyl-methyl)-amide.84. The compound of claim 43, wherein R⁵ is 3-hydroxy-phenyl.
 85. Thecompound of claim 84, wherein R¹ is —CO—R^(a).
 86. The compound of claim85, which is trans-2-(2-thiophen-2-yl-acetylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide.
 87. The compound of claim85, wherein R^(a) is cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyloxy,aryl, aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, or heteroaryl-lower-alkoxy. 88.The compound of claim 87, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-thiophen-2-yl-propyl ester.
 89. The compound of claim 87, whichistrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-p-tolyl-propyl ester.
 90. The compound of claim 87, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-(4-chloro-phenyl)-propyl ester.
 91. The compound of claim 87,which is trans-2-(2-phenylsulfanyl-acetylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide.
 92. The compound of claim87, wherein R^(a) is cycloalkyl.
 93. The compound of claim 87, whereinR^(a) is aryl-lower-alkyl.
 94. The compound of claim 87, wherein R^(a)is aryloxy-lower-alkyl.
 95. The compound of claim 94, which istrans-2-(2-phenoxy-acetylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide.
 96. The compound of claim 87,wherein R^(a) is phenyl optionally substituted with at least one groupselected from phenyl, cyano and fluoro; or R^(a) is benzyloxy optionallysubstituted with at least one group selected from methyl, chloro,fluoro, methoxy, nitro, and CF₃; or R^(a) is phenylvinylene,thiophenyl-methylene-oxy, cyclopentyloxy, thiophenyl-ethylene-oxy,naphthyloxy, thiophenyl-trimethylene-oxy, or phenoxy.
 97. The compoundof claim 96 wherein R^(a) is phenyl optionally substituted with at leastone group selected from phenyl, cyano and fluoro.
 98. The compound ofclaim 97, which istrans-N-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-4-fluoro-benzamide.99. The compound of claim 96, wherein R^(a) is benzyloxy optionallysubstituted with at least one group selected from methyl, chloro,fluoro, methoxy, nitro and CF₃.
 100. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-methyl-benzyl ester.
 101. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-chloro-benzyl ester.
 102. The compound of claim 99, which is(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-fluoro-benzyl ester.
 103. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-methoxy-benzyl ester.
 104. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-chloro-benzyl ester.
 105. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-methyl-benzyl ester.
 106. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 3-methoxy-benzyl ester.
 107. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-methyl-benzyl ester.
 108. The compound of claim 99, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-methoxy-benzyl ester.
 109. The compound of claim 96, whereinR^(a) is phenylvinylene, thiophenyl-methylene-oxy, cyclopentyloxy,thiophenyl-ethylene-oxy, naphthyloxy, thiophenyl-trimethylene-oxy, orphenoxy.
 110. The compound of claim 109, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 2-thiophen-2-yl-ethyl ester.
 111. The compound of claim 109, whichis (2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-trifluoromethyl-benzyl ester.
 112. The compound of claim 96,wherein R^(a) is benzyloxy, phenylvinylene, thiophen-2-yl-methylene-oxy,or thiophen-3-yl-methylene-oxy.
 113. The compound of claim 112, which is(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-3-ylmethyl ester.
 114. The compound of claim 112, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid thiophen-2-ylmethyl ester.
 115. The compound of claim 112, whereinR^(a) is benzyloxy.
 116. The compound of claim 115, which is(1R,2R)-(2-{(S)-[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 117. The compound of claim 115, which iscis-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 118. The compound of claim 115, which istrans-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 119. The compound of claim 115, which is(1R,2R)-(2-{(R)-[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 120. The compound of claim 87, wherein R^(a) isbenzyl optionally substituted with chloro, or phenyl optionallysubstituted with lower-alkyl, lower-alkoxy, or cyano.
 121. The compoundof claim 120, wherein R^(a) is 4-ethyl-phenyl, 4-methoxy-phenyl,4-ethoxy-phenyl, 4-cyano-phenyl, 4-tert.-butyl-phenyl, or4-chloro-benzyl.
 122. The compound of claim 121, which istrans-4-cyano-N-(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-benzamide.123. The compound of claim 121, which iscis-2-(4-ethoxy-phenylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide.
 124. The compound of claim 85,wherein R^(a) is heteroaryl.
 125. The compound of claim 124, which istrans-isoxazole-5-carboxylic acid(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide. 126.The compound of claim 124 which is trans-thiophene-2-carboxylic acid(2-{[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide. 127.The compound of claim 87, wherein R^(a) is 5-methoxy-benzofuran-2-yl.128. The compound of claim 84, wherein R¹ is —SO₂—R^(b).
 129. Thecompound of claim 128, which istrans-2-(4-chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide.
 130. The compound of claim 128,which is trans-2-phenylmethanesulfonylamino-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide.
 131. The compound of claim 128,which is trans-2-(4-cyano-benzenesulfonylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide.
 132. The compound of claim128, which istrans-2-(4-acetylamino-benzenesulfonylamino)-cyclohexanecarboxylic acid[cyano-(3-hydroxy-phenyl)-methyl]-amide.
 133. The compound of claim 128,which istrans-2-(benzo[1,2,5]oxadiazole-4-sulfonylamino)-cyclohexanecarboxylicacid [cyano-(3-hydroxy-phenyl)-methyl]-amide.
 134. The compound of claim84, wherein R¹ is phenyl, optionally substituted with ethoxy.
 135. Thecompound of claim 43, wherein R⁵ is 3-methoxy-phenyl.
 136. The compoundof claim 135, which is cis-(2-{(R)- and(S)-[cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 137. The compound of claim 135, which is(1S,2R)-(2-(R)- and(S)-{[cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 138. The compound of claim 135, which istrans-(2-{[cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 139. The compound of claim 43, wherein R⁵ is4-methoxy-phenyl.
 140. The compound of claim 139, which is cis-(2-{(R)-and(S)-[cyano-(4-methoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 141. The compound of claim 139, which iscis-2-(4-ethoxy-phenylamino)-cyclohexanecarboxylic acid[cyano-(4-methoxy-phenyl)-methyl]-amide.
 142. The compound of claim 43,wherein R⁵ is 3-methyl-phenyl.
 143. The compound of claim 142, which iscis-{2-[(R)- and(S)-(cyano-m-tolyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acid benzylester.
 144. The compound of claim 43, wherein R⁵ is2,4-dimethoxy-phenyl.
 145. The compound of claim 144, which iscis-(2-{(R)- and(S)-[cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 146. The compound of claim 43, wherein R⁵ is3,4-dimethoxy-phenyl.
 147. The compound of claim 146, wherein R¹ is—CO—R^(a).
 148. The compound of claim 147, which iscis-2-(2-benzyloxy-acetylamino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 149. The compound ofclaim 147, wherein R^(a) is cycloalkyl, cycloalkyl-lower-alkyl,cycloalkyloxy, aryl, aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy,aryloxy-lower-alkyl, aryl-S-lower-alkyl, aryl-lower-alkenyl, orheteroaryl-lower-alkoxy.
 150. The compound of claim 149, which iscis-2-(3-cyclopentyl-propionylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 151. The compound ofclaim 149, which iscis-2-(2-phenylsulfanyl-acetylamino)-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 152. The compound ofclaim 149, wherein R^(a) is cycloalkyl.
 153. The compound of claim 152,which is cis-2-(cyclopropanecarbonyl-amino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 154. Thecompound of claim 152, which iscis-2-(3-cyclohexylcarbonylamino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 155. The compound ofclaim 152, which iscis-2-(cyclobutanecarbonyl-amino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 156. The compound ofclaim 152, which iscis-2-(cyclopentanecarbonyl-amino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 157. The compound ofclaim 149, wherein R^(a) is aryl-lower-alkyl.
 158. The compound of claim157, which is cis-2-(3-phenyl-propionylamino)-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 159. Thecompound of claim 149, wherein R^(a) is aryloxy-lower-alkyl.
 160. Thecompound of claim 159, which iscis-2-(2-phenoxy-acetylamino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 161. The compound ofclaim 159, which iscis-2-[2-(4-chloro-phenoxy)-acetylamino]-cyclohexanecarboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 162. Thecompound of claim 149, wherein R^(a) is phenyl optionally substitutedwith at least one group selected from phenyl, cyano, and fluoro; orR^(a) is benzyloxy optionally substituted with at least one groupselected from methyl, chloro, fluoro, methoxy, nitro, and CF₃; or R^(a)is phenylvinylene, thiophenyl-methylene-oxy, cyclopentyloxy,thiophenyl-ethylene-oxy, naphthyloxy, thiophenyl-trimethylene-oxy, orphenoxy.
 163. The compound of claim 162, which is cis-(2-{[(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid cyclopentyl ester.
 164. The compound of claim 162, which iscis-biphenyl-4-carboxylic acid (2-{[(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-amide.165. The compound of claim 162, which is cis-(2-{[(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid 4-nitro-benzyl ester.
 166. The compound of claim 162, wherein R^(a)is benzyloxy, phenylvinylene, thiophen-2-yl-methylene-oxy, orthiophen-3-yl-methylene-oxy.
 167. The compound of claim 166, which iscis-2-(3-phenyl-acryloylamino)-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 168. The compound ofclaim 166, wherein R^(a) is benzyloxy.
 169. The compound of claim 168,which is(2-{[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester (1 cis-racemate).
 170. The compound of claim 168,which is(2-{[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester (1 cis-racemate).
 171. The compound of claim 149,wherein R^(a) is benzyl optionally substituted with chloro, or phenyloptionally substituted with lower-alkyl, lower-alkoxy, or cyano. 172.The compound of claim 171, which iscis-2-phenylacetylamino-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 173. The compound ofclaim 171, which iscis-2-[2-(4-chloro-phenyl)-acetylamino]-cyclohexanecarboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 174. The compound ofclaim 171, wherein R^(a) is 4-ethyl-phenyl,4-methoxy-phenyl,4-ethoxy-phenyl, 4-cyano-phenyl, 4-tert.-butyl-phenyl, or4-chloro-benzyl.
 175. The compound of claim 147, wherein R^(a) isheteroaryl.
 176. The compound of claim 175, wherein R^(a) is5-methoxy-benzofuran-2-yl.
 177. The compound of claim 146, wherein R¹ is—SO₂—R^(b).
 178. The compound of claim 177, which iscis-2-phenylmethanesulfonylamino-cyclohexanecarboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 179. The compound ofclaim 177, wherein R¹ is phenyl, optionally substituted with ethoxy.180. The compound of claim 179, which is cis-N-(2-{[(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-cyclohexyl)-benzamide.181. The compound of claim 43, wherein R⁵ is 3-chloro-phenyl.
 182. Thecompound of claim 181, which is cis-(2-{(R)- and(S)-[(3-chloro-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 183. The compound of claim 43, wherein R⁵ is3-bromo-phenyl.
 184. The compound of claim 183, which istrans-(2-{[(3-bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid benzyl ester.
 185. The compound of claim 183, which is(2-{[(3-bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamic acidbenzyl ester.
 186. The compound of claim 183, which iscis-2-(4-ethoxy-phenylamino)-cyclohexanecarboxylic acid[(3-bromo-phenyl)-cyano-methyl]-amide.
 187. The compound of claim 43,wherein R⁵ is 4-bromo-phenyl.
 188. The compound of claim 187, which iscis-(2-{(R)- and(S)-[(4-bromo-phenyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-carbamicacid.
 189. The compound of claim 43, wherein R⁵ isbenzo[1,3]dioxol-5-yl.
 190. The compound of claim 189, which istrans-{2-[(benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester.
 191. The compound of claim 189, which iscis-{2-[(benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-cyclohexyl}-carbamicacid benzyl ester.
 192. The compound of claim 189, which iscis-2-(4-ethoxy-phenylamino)-cyclohexanecarboxylic acid (benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 193. The compound of claims 189,which is cis-2-phenylamino-cyclohexanecarboxylic acid (benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 194. The compound of claim 22,wherein R⁵ is hydrogen.
 195. The compound of claim 194, wherein R¹ is—CO—R^(a).
 196. The compound of claim 195, wherein R^(a) is cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyloxy, aryl, aryloxy, aryl-lower-alkyl,aryl-lower-alkoxy, aryloxy-lower-alkyl, aryl-S-lower-alkyl,aryl-lower-alkenyl, or heteroaryl-lower-alkoxy.
 197. The compound ofclaim 196, wherein R^(a) is aryl.
 198. The compound of claim 197, whichis cis-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-bromo-benzyl ester.
 199. The compound of claim 197, which istrans-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-bromo-benzyl ester.
 200. The compound of claim 197, wherein R^(a) isphenyl, optionally substituted with at least one of lower-alkyl,fluorine, —CF₃, -SCH₃, acetylamino, chlorine, bromine, hydroxy, cyano,lower-alkoxy, lower-alkylcarbonyloxy, phenyl, phenoxy, aryl-lower-alkylor aryl-lower-alkoxy.
 201. The compound of claim 200, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2-chloro-4-fluoro-benzamide.202. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-fluoro-4-methyl-benzamide.203. The compound of claim 200, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4-cyanomethyl-benzamide.204. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3,5-di-trifluoromethyl-benzamide.205. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4-tert-butyl-benzamide.206. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-acetylamino -benzamide.207. The compound of claim 200, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-acetylamino -benzamide.208. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4- acetylamino -benzamide.209. The compound of claim 200, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4-acetylamino -benzamide.210. The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4-acetyl -benzamide. 211.The compound of claim 200, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-4-acetyl -benzamide. 212.The compound of claim 200, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2-chloro-5-(methylthio)-benzamide.213. The compound of claim 200, wherein R^(a) is phenyl, optionallysubstituted with at least one of hydroxy, methyl, chlorine, bromine ormethoxy.
 214. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2-methoxy-3-methyl-benzamide.215. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,6-dichloro-4-methoxy-benzamide.216. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-4-methyl-benzamide.217. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-bromo-4-methyl-benzamide.218. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-6-methoxy-benzamide.
 219. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro-6-methoxy-benzamide.220. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3-chloro -benzamide. 221.The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,3-dichloro- benzamide.222. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,3-dichloro-benzamide.223. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,4-dichloro-benzamide.224. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,5-dichloro-benzamide.225. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-2,6-dichloro-benzamide.226. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3,4-dichloro-benzamide.227. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3,4-dichloro-benzamide.228. The compound of claim 213, which iscis-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3,5-dichloro-benzamide.229. The compound of claim 213, which istrans-N-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-3,5-dichloro-benzamide.230. The compound of claim 196, wherein R^(a) is cycloalkyl.
 231. Thecompound of claim 196, wherein R^(a) is aryl-lower-alkyl.
 232. Thecompound of claim 196, wherein R^(a) is aryloxy-lower-alkyl.
 233. Thecompound of claim 196, wherein R^(a) is phenylvinylene,thiophenyl-methylene-oxy, cyclopentyloxy, thiophenyl-ethylene-oxy,naphthyloxy, thiophenyl-trimethylene-oxy, or phenoxy.
 234. The compoundof claim 233, which istrans-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid phenyl ester.235. The compound of claim 196, wherein R^(a) is benzyloxy optionallysubstituted with at least one group selected from methyl, chloro,fluoro, methoxy, nitro and CF₃.
 236. The compound of claim 235, whereinR^(a) is benzyloxy substituted with methyl.
 237. The compound of claim235, wherein R^(a) is benzyloxy substituted with chloro.
 238. Thecompound of claim 237, which iscis-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid 2-chloro-benzylester.
 239. The compound of claim 237, which iscis-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid 4-chloro-benzylester.
 240. The compound of claim 237, which iscis-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3,4-dichloro-benzyl ester.
 241. The compound of claim 237, which iscis-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid 3-chloro-benzylester.
 242. The compound of claim 237, which istrans-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid2-chloro-benzyl ester.
 243. The compound of claim 237, which istrans-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3,4-dichloro-benzyl ester.
 244. The compound of claim 235, wherein R^(a)is benzyloxy substituted with fluoro.
 245. The compound of claim 235,wherein R^(a) is benzyloxy substituted with methoxy.
 246. The compoundof claim 235, wherein R^(a) is benzyloxy substituted with nitro. 247.The compound of claim 246, which iscis-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid 3-nitro-benzylester.
 248. The compound of claim 246, which istrans-[4-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid3-nitro-benzyl ester.
 249. The compound of claim 235, wherein R^(a) isbenzyloxy substituted with CF₃.
 250. The compound of claim 196, whereinR^(a) is benzyloxy, phenylvinylene, thiophen-2-yl-methylene-oxy, orthiophen-3-yl-methylene-oxy.
 251. The compound of claim 250, whereinR^(a) is benzyloxy.
 252. The compound of claim 251, which istrans-[2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid benzyl ester.253. The compound of claim 196, wherein R^(a) is benzyl optionallysubstituted with chloro, or phenyl optionally substituted withlower-alkyl, lower-alkoxy, or cyano.
 254. The compound of claim 253,wherein R^(a) is 4-ethyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl,4-cyano-phenyl, 4-tert.-butyl-phenyl, or 4-chloro-benzyl.
 255. Thecompound of claim 195, wherein R^(a) is heteroaryl.
 256. The compound ofclaim 255, which is cis-5-methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide.
 257. The compound of claim255, which is trans-5-methoxy-benzofuran-2-carboxylic acid[2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide.
 258. The compound of claim255, wherein R^(a) is 5-methoxy-benzofuran-2-yl.
 259. The compound ofclaim 194, wherein R¹ is —SO₂—R^(b).
 260. The compound of claim 194,wherein R¹ is phenyl, optionally substituted with ethoxy.
 261. Thecompound of claim 22, wherein R⁵ is cycloalkyl.
 262. The compound ofclaim 261, wherein R⁵ is cyclopropyl.
 263. The compound of claim 262,wherein R¹ is —CO—R^(a).
 264. The compound of claim 263, wherein R^(a)is cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyloxy, aryl, aryloxy,aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, or heteroaryl-lower-alkoxy. 265.The compound of claim 264, wherein R^(a) is cycloalkyl.
 266. Thecompound of claim 264, wherein R^(a) is aryl-lower-alkyl.
 267. Thecompound of claim 266, which iscis-N-[cyano(cyclopropyl)methyl]-2-{[3-(3-methoxyphenyl)propanoyl]amino}cyclohexanecarboxamide.268. The compound of claim 264, wherein R^(a) is aryloxy-lower-alkyl.269. The compound of claim 264, wherein R^(a) is phenyl optionallysubstituted with at least one group selected from phenyl, cyano, andfluoro; or R^(a) is benzyloxy optionally substituted with at least onegroup selected from methyl, chloro, fluoro, methoxy, nitro, and CF₃; orR^(a) is phenylvinylene, thiophenyl-methylene-oxy, cyclopentyloxy,thiophenyl- ethylene- oxy, naphthyloxy, thiophenyl-trimethylene-oxy, orphenoxy.
 270. The compound of claim 269, which iscis-N-[2-({[cyano(cyclopropyl)methyl]-amino}carbonyl)cyclohexyl]-3,4-difluorobenzamide.271. The compound of claim 269, wherein R^(a) is benzyloxy,phenylvinylene, thiophen-2-yl-m ethylene-oxy, orthiophen-3-yl-methylene-oxy.
 272. The compound of claim 271, whereinR^(a) is benzyloxy.
 273. The compound of claim 272, which iscis{2-[(cyano-cyclopropyl-methyl)-carbamoyl]-cyclohexyl}-carbamic acidbenzyl ester.
 274. The compound of claim 264, wherein R^(a) is benzyloptionally substituted with chloro, or phenyl optionally substitutedwith lower-alkyl, lower-alkoxy, or cyano.
 275. The compound of claim274, which iscis-2-{[(4-chlorophenyl)acetyl]amino}-N-[cyano(cyclopropyl)methyl]cyclo-hexanecarboxamide.276. The compound of claim 274, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-3,4,5-trimethoxybenzamide.
 277. The compound of claim 274,wherein R^(a) is 4-ethyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl,4-cyano-phenyl, 4-tert.-butyl-phenyl, or 4-chloro-benzyl.
 278. Thecompound of claim 277, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide.279. The compound of claim 277, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzamide.280. The compound of claim 277, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide.281. The compound of claim 277, which istrans-N-[2-({[cyano(cyclopropyl)-methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide.282. The compound of claim 277, which istrans-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide.283. The compound of claim 277, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert-butylbenzamide.
 284. The compound of claim277, which iscis-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzamide.285. The compound of claim 263, wherein R^(a) is heteroaryl.
 286. Thecompound of claim 285, wherein R^(a) is 5-methoxy-benzofuran-2-yl. 287.The compound of claim 262, wherein R¹ is —SO₂—R^(b).
 288. The compoundof claim 262, wherein R¹ is phenyl, optionally substituted with ethoxy.289. An isolated stereoisomer selected from the group consisting ofcompounds of formula (Ia)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2;pharmaceutically acceptable salts of compounds of formula (Ia); andpharmaceutically acceptable esters of compounds of formula (Ia).
 290. Anisolated stereoisomer selected from the group consisting of compounds offormula (Ib)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R²is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2;pharmaceutically acceptable salts of compounds of formula (Ib); andpharmaceutically acceptable esters of compounds of formula (Ib).
 291. Anisolated stereoisomer selected from the group consisting of compounds offormula (Ic)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2;pharmaceutically acceptable salts of compounds of formula (Ic); andpharmaceutically acceptable esters of compounds of formula (Ic).
 292. Aprocess for the manufacture of compounds compounds of formula (I)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2; the processcomprising: reacting a compound of formula (II)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl,and n is 1 or 2; with a compound of formula (III)

wherein R³ is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl,and R⁵ is hydrogen, lower-alkyl, cycloalkyl, or aryl; to form thecompound of formula (I).
 293. A process for the manufacture of compoundscompounds of formula (I)

wherein R¹ is hydrogen, aryl, —CO—R^(a) or —SO₂—R^(b), wherein R^(a)represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, R² is hydrogen or lower-alkyl, R³is hydrogen or lower-alkyl, R⁴ is hydrogen or lower-alkyl, R⁵ ishydrogen, lower-alkyl, cycloalkyl, or aryl, and n is 1 or 2; the processcomprising: reacting a compound of formula (IV)

wherein R² is hydrogen or lower-alkyl, R³ is hydrogen or lower-alkyl, R⁴is hydrogen or lower-alkyl, R⁵ is hydrogen, lower-alkyl, cycloalkyl, oraryl, and n is 1 or 2; with a compound of formula (V) or (VI)

wherein R^(a) represents lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl,aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl,aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl,heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy, and R^(b) representsaryl, aryl-lower-alkyl, or heteroaryl, to form the compound of formula(I).
 294. A method for treatment of a human or animal havingosteoporosis, instable angina pectoris and/or plaque rupture, comprisingadministering a therapeutically effective amound of the compound ofclaim 1 to the human or animal.